Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([CH2:21][N:22]3[CH2:26][CH2:25][CH:24]([NH:27]C(OC(C)(C)C)=O)[C:23]3=[O:35])=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.CCN(CC)CC.[Cl:50][C:51]1[CH:52]=[CH:53][C:54]2[CH:58]=[C:57]([S:59](Cl)(=[O:61])=[O:60])[S:56][C:55]=2[CH:63]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([CH2:21][N:22]3[CH2:26][CH2:25][CH:24]([NH:27][S:59]([C:57]4[S:56][C:55]5[CH:63]=[C:51]([Cl:50])[CH:52]=[CH:53][C:54]=5[CH:58]=4)(=[O:61])=[O:60])[C:23]3=[O:35])=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)C1=O
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCc2ccc(CN3CCC(NS(=O)(=O)c4cc5ccc(Cl)cc5s4)C3=O)cc2C1
Reaction time: 4 h
Yield: 70.8 %

Procedure:
To a solution of 7-(3-tert-butoxycarbonylamino-2-oxopyrrolidin-1-ylmethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (0.347 g, 0.72 mmol) in 8 mL of CH2Cl2 is added 2 mL of TFA. After 4 hours, the solution is concentrated. The residue is dissolve in CH2Cl2 and Et3N (0.30 mL, 2.17 mmol) and 6-chloro benzo[b]thiophene sulfonyl chloride (0.23 g, 0.87 mmol) are added. After 16 hours, the solution is concentrated. The residue is purified by column chromatography eluting with 10% EtOAc/CH2Cl2. The product (0.25 g, 0.51 mmol) was obtained as a white solid.
Reaction SMILES: C[O-].[Na+].[N:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=O)=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[CH3:27][NH2:28]>CO.C(O)C>[CH3:27][NH:28][C:20]([C:19]1[CH:18]=[CH:17][C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:8]=[CH:9][N:4]=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)=[CH:26][CH:25]=1)=[O:22]
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: CN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CNC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A 2M solution of sodium methoxide in methanol (0.89 ml) was added to a suspension of ethyl 4-[4-(4-pyridyl)-1-piperazinyl]benzoate (500 mg) in a 33% solution of monomethylamine in ethanol (15 ml). The mixture was stirred at 40° C. for 18 hours. The mixture was cooled and the solid was collected by filtration. The solid was washed with ethanol and ether to give 1-(4-methylcarbamoylphenyl)-4-(4-pyridyl) piperazine (374 mg) as a cream solid, mp 239-242° C.
Reaction SMILES: C1(COC([NH:11][NH:12][C:13]([NH:15][NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=2)=[O:14])=O)C=CC=CC=1.CO.[ClH:29].CCOCC>[Pd]>[ClH:29].[NH:12]([C:13]([NH:15][NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=1)=[O:14])[NH2:11]
Reactant: O=C(NNC(=O)OCc1ccccc1)NNC(=O)c1ccc(O)c(O)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NNC(=O)NNC(=O)c1ccc(O)c(O)c1

Procedure:
A solution of 3.60 g (10.0 mmol) of 3,4-dihydroxybenzoic acid, 2-[[2-[(phenylmethoxy)carbonyl]hydrazino]carbonyl]hydrazide in 90 ml of dry methanol containing 1.67 ml (20.0 mmol) of concentrated hydrochloric acid was hydrogenated in the presence of 0.36 g of 10% palladium on charcoal for 15 minutes. After the removal of the catalyst by filtration and of the solvent by evaporation in vacuo, the crude solid (2.61 g) was stirred with a few ml of dry ether; yield: 2.41 g.
Reaction SMILES: [I-].[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Zn+])=[CH:9][CH:8]=1)=[O:6])[CH3:3].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:10]1[CH:11]=[CH:12][C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1ccc([Zn+])cc1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(Ethoxycarbonyl)phenylzinc iodide in tetrahydrofuran (0.5M, 2 mL, 1 mmol) was added to a solution of 2-bromopyridine (0.16 g, 1 mmol) and tetrakis(triphenylphosphine)palladium(0) (63 mg, 0.05 mmol) in tetrahydrofuran (5 mL) and stirred at RT for 3 h. The reaction was quenched with saturated ammonium chloride and extracted three times with ethyl acetate. The combined organic phase was dried (MgSO4), concentrated in vacuo, and the residue chromatographed (silica gel, 10% ethyl acetate/hexane) to give the title compound as a yellow solid (0.15 g).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14]O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].O=S(Cl)[Cl:20]>>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14][Cl:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCC[C@H]1CC[C@H](c2ccc(CO)cc2)CC1
Product: CCC[C@H]1CC[C@H](c2ccc(CCl)cc2)CC1

Procedure:
114 g (0.49 mol) of 4-(trans-4'-propylcyclohexyl) benzyl alcohol was dissolved in 107 cm3 (1.05 mol) of SOCl2 and the solution was refluxed over a warm water bath for 5 hours. The excess SOCl2 was distilled off under reduced pressure and the residue was washed with 10% hydrochloric acid and water. The chloroform was distilled off under reduced pressure and the residue was distilled under reduced pressure (147° C./3.0 mmHg) to yield 114 g (0.45 mol) of 4-(trans-4'-propylcyclohexyl)-benzyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:11]Br>C(O)(=O)C>[Br:11][C:7]1[C:8]([OH:10])=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: BrBr
Reactant: O=Cc1ccc(O)cc1F
Solvent: CC(=O)O
Product: O=Cc1cc(Br)c(O)cc1F
Temperature: 45 °C
Reaction time: 26 h
Yield: 34.9 %

Procedure:
To a solution of 2-fluoro-4-hydroxybenzaldehyde (2.2 g, 15.7 mmol, 1 eq) in acetic acid (70 mL) was added a solution of bromine (2.71 g, 17.0 mmol, 1.1 eq) in acetic acid (10 mL), and the mixture was stirred at 45° C. for 26 h. The reaction was concentrated in vacuo, brine (50 mL) was added, and the mixture was extracted with EtOAc (3×80 mL). The combined organic layers were dried (Na2SO4), concentrated in vacuo. The resultant residue was purified by silica gel chromatography (DCM:MeOH=15:1 to 5:1) to afford 1.2 g (35%) of 5-bromo-2-fluoro-4-hydroxybenzaldehyde (25).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:20])[NH:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[N+:21]([O-])=O.CCO.O.C(=O)(O)[O-].[Na+]>Cl.[Fe].CCOC(C)=O>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:20])[NH:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[NH2:21]
Reactant: CCNC(=O)c1ccc(Sc2ccc([N+](=O)[O-])c(Cl)c2F)cc1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCNC(=O)c1ccc(Sc2ccc(N)c(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78.5 %

Procedure:
2-Chloro-3-fluoro-4-[4-(N-ethylcarbamoyl)phenylsulphanyl]nitrobenzene (Method 82; 360 mg, 1.02 mmol), iron powder (617 mg), EtOH (0.68 ml), water (0.28 ml) and 1 drop of conc. HCl were heated at 75° C. with stirring for 45 minutes. The mixture was allowed to cool to room temp and then made basic using saturated sodium bicarbonate solution. EtOAc was added and the solution was poured onto a Chem Elut column and eluted with EtOAc to yield the title compound (260 mg) as a pale yellow sticky solid. NMR: 1.1 (t, 3H), 3.2 (q, 2H), 6.1 (s, 1H), 7.0 (q, 2H), 7.2 (q, 1H), 7.7 (t, 2H), 8.3 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[OH:13][C@:14]([CH3:50])([CH2:48][OH:49])[C:15](=[O:47])[C@@H:16]([NH:24][C:25](=[O:46])[C@@H:26]([NH:30][C:31](=[O:45])[C@@H:32]([NH:36][C:37]([C:39]1[S:43][C:42]([CH3:44])=[N:41][CH:40]=1)=[O:38])[CH2:33][O:34][CH3:35])[CH2:27][O:28][CH3:29])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([O:49][CH2:48][C@:14]([OH:13])([CH3:50])[C:15](=[O:47])[C@@H:16]([NH:24][C:25](=[O:46])[C@@H:26]([NH:30][C:31](=[O:45])[C@@H:32]([NH:36][C:37]([C:39]1[S:43][C:42]([CH3:44])=[N:41][CH:40]=1)=[O:38])[CH2:33][O:34][CH3:35])[CH2:27][O:28][CH3:29])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:11])=[O:10]
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)COS(=O)(=O)c1ccc(F)cc1F

Procedure:
Prepared according to procedures described above, by reacting 2,4-difluorobenzenesulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C31H36F2N4O10S2 m/z: 727 (M+H)+.
Reaction SMILES: N1CCCCC1.[F:7][C:8]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:9]=1[CH:10]=O.C(O)(=O)[CH2:18][C:19]([OH:21])=[O:20].Cl>N1C=CC=CC=1>[F:7][C:8]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:9]=1[CH:10]=[CH:18][C:19]([OH:21])=[O:20]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(F)ccc1F
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cc(F)ccc1F
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 85.6 %

Procedure:
Piperidine (2 mL, 20.2 mmol, 0.168 vol) was added to a stirred mixture of 2,5-difluorobenzaldehyde (12.07 g, 85.0 mmol, 1 wt) and malonic acid (18.28 g, 175.6 mmol, 1.51 wt) in pyridine (50 mL, 4.14 vol). The reaction mixture was heated under nitrogen and held at reflux (oil bath 100° C.) for 2 hours, effervescence was observed for about 90 minutes—initially vigorous then diminishing. The reaction mixture was then allowed to cool to 20 to 25° C. and poured into stirred 2 M hydrochloric acid (310 mL, 25.7 vol) (pH recorded as 1). The resulting precipitate was aged at 20 to 25° C. for 1 hour then filtered. The filter cake was washed with water (2×50 mL, 4.1 vol) then left to dry for a further 1 hour. The solid product was dried by dissolving it in TBME (250 mL, 20.7 vol), separating the phases and the water phase washed with TBME (100 mL, 8.3 vol). The TBME phases were combined, dried over magnesium sulphate (25 g, 2 wt), filtered and concentrated on a rotary evaporator to afford the product as a white solid (13.4 g, 85.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:21][C:20](=[O:22])[NH:19][N:18]=2)[CH2:13][CH2:12]1.[CH2:23](Br)[CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:23]([N:19]1[N:18]=[C:17]([CH:14]2[CH2:15][CH2:16][N:11]([C:3]3[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[F:1])[CH2:12][CH2:13]2)[O:21][C:20]1=[O:22])[CH3:24]
Reactant: CCBr
Reactant: O=c1[nH]nc(C2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1nc(C2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)oc1=O
Temperature: 0 °C
Yield: 94.4 %

Procedure:
5-[1-(2-Fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5b, 1.23 g, 4 mmol) on reacting with C2H5Br (0.53 g, 4.8 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at room temperature (27° C.) for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 3-ethyl-5-[1-(2-fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (6e, 1.27 g, 95%). Nitro compound (6e, 1.34 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution, is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-amino-2-fluorophenyl)-4-piperidyl]-3-ethyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7 g, 1.05 g, 86%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzo triazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodi imide)) (0.19 g, 1 mmol) and amine compound (7g, 0.3 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(4-ethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]-3-fluorophenyl-5-nitro-2-furamide (8 g, 391 mg, 88%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(CC)CC.Cl[C:23]([O:25][CH3:26])=[O:24].OS([O-])(=O)=O.[K+]>C(Cl)Cl>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 638.8 %

Procedure:
A solution of 4.00 g (2.00 mmol) of 4-amino-1-BOC-piperidine and 4.18 ml (3.00 mmol) of Et3N in 50 ml of CH2Cl2 was treated at 0° C. with 1.62 ml (2.10 mmol) of methyl chloroformate. The reaction was stirred for 16 h at RT, neutralized with aqueous 10% KHSO4 and extracted with CH2Cl2 (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (n- heptane/EtOAc 1:1 to 1:2) to yield 3.30 g (64%) of the title compound as white solid. MS: 259.2 (MH+).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23](OC)=[O:24]>O1CCCC1.CCCCCC.C(O)(=O)C>[O:24]=[C:23]([CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)Cc1cccs1
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)Cc1cccs1)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.9 %

Procedure:
A solution of 37.2 g (0.3 mole) dimethyl methylphosphonate (Aldrich) in 400 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 194 ml of 1.6 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 23.4 g (0.15 mole) methyl 2-(2-thienyl)acetate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 3.5 hours at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 6 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 75 ml water the aqueous phase extracted with 100 ml portions of chloroform (3x) the combined organic extracts were backwashed (50 ml H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 150°-152° (<0.5 mm) to give 4.8 g dimethyl 2-oxo-3-(2-thienyl)propylphosphonate (2a).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([OH:12])=[O:11])[N:9]=1.[CH3:13]I.[OH-].[Na+].Cl>CN(C=O)C.O>[CH3:13][O:3][CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([OH:12])=[O:11])[N:9]=1
Reactant: O=C(O)c1csc(CO)n1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1nc(C(=O)O)cs1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (0.151 g, 3.77 mmol) was added to a solution of 2-(hydroxymethyl)thiazole-4-carboxylic acid (0.2 g, 1.26 mmol) in DMF (2 mL) and stirred for 20 min. Methyl iodide (0.236 mL, 3.77 mmol) was added and the reaction stirred for a further 2 h. Water (2 mL) was added, followed by NaOH (0.251 g, 6.28 mmol) and stirred for 20 h. The reaction mixture was heated at 60° C. for 5 h then cooled to RT, acidified with 2M HCl and purified by reverse phase HPLC with MeCN/aqTFA as eluent to afford the sub-title compound as a white solid. Yield: 31 mg
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:16]([C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)=O)=[CH:13][C:12]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[C:11]([O:34][CH3:35])[CH:10]=2.O.O.[Sn](Cl)Cl>O.Cl>[CH2:27]([O:26][C:12]1[C:11]([O:34][CH3:35])=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:5][N:1]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=4)[C:15]=3[C:14]=2[CH:13]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc2ncc(N)c(C(=O)c3ccc(C#N)cc3)c2cc1OCc1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1cc2ncc3[nH]nc(-c4ccc(C#N)cc4)c3c2cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
A solution of sodium nitrite (483 mg, 6.99 mmol) in water (2.5 ml) is added dropwise over the course of 1.5 h at (−)1-0° C. to a suspension of 4-(3-amino-6-benzyloxy-7-methoxy-quinoline-4-carbonyl)benzonitrile (2.60 g, 6.35 mmol) in concentrated hydrochloric acid (50 ml). The mixture is subsequently stirred for a further 30 min. A solution of tin(II) chloride dihydrate (5.02 g, 22.23 mmol) in concentrated hydrochloric acid (3.8 ml) is then added at (−)5° C. The suspension obtained is stirred at room temperature for 1 h, subsequently diluted with water (500 ml), stirred for 30 min and filtered with suction. The filter cake is rinsed with water and dried in a high vacuum, giving 4-(8-benzyloxy-7-methoxy-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (2.42 g, 5.95 mmol) as a solid having a melting point of 222.8° C. (decomposition). MS: 407.1 (M+H+), TLC (HPTLC): Rf=0.27 (ethyl acetate).
Reaction SMILES: COC1C=C(C=C([N+]([O-])=O)C=1)C=O.C(NC(C1CCNCC1)=O)(C)(C)C.[C:27]([NH:31][C:32]([CH:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]2[CH:46]=[C:45]([N+:47]([O-])=O)[CH:44]=[C:43]([O:50][CH3:51])[CH:42]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][C:32]([CH:34]1[CH2:35][CH2:36][N:37]([CH2:40][C:41]2[CH:42]=[C:43]([O:50][CH3:51])[CH:44]=[C:45]([NH2:47])[CH:46]=2)[CH2:38][CH2:39]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: COc1cc(CN2CCC(C(=O)NC(C)(C)C)CC2)cc([N+](=O)[O-])c1
Agent: CC(C)(C)NC(=O)C1CCNCC1
Agent: COc1cc(C=O)cc([N+](=O)[O-])c1
Product: COc1cc(N)cc(CN2CCC(C(=O)NC(C)(C)C)CC2)c1

Procedure:
The title compound is prepared according to the reactions described for BB-5 above starting from 3-methoxy-5-nitro-benzaldehyde and piperidine-4-carboxylic acid tert-butylamide yielding after reductive amination 1-(3-methoxy-5-nitro-benzyl)-piperidine-4-carboxylic acid tert-butylamide; LC-MS A: tR=0.63 min; [M+H]+=350.14 followed by reduction with stannous chloride the title compound; LC-MS A: tR=0.50 min; [M+H]+=320.19.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[CH:11][C:10]([C:14](F)=[O:15])=[N:9]1.C([O-])([O-])=O.[K+].[K+].[C:34]1([S:40]([NH2:43])(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]([NH:43][S:40]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:42])=[O:41])=[O:15])=[N:9]1
Reactant: COc1ccc(COc2ccc(Cl)cc2Cn2nc(C(=O)F)cc2C)cc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(COc2ccc(Cl)cc2Cn2nc(C(=O)NS(=O)(=O)c3ccccc3)cc2C)cc1
Reaction time: 16 h

Procedure:
To a solution of 1-[5-chloro-2-(4-methoxy-benzyloxy)-benzyl]-5-methyl-1H-pyrazole-3-carbonyl fluoride, 15, 0.06 g (0.18 mmol) and K2CO3 0.100 g (0.72 mmol) in dry DCM (2 mL), benzenesulfonamide 0.055 g (0.35 mmol) was added. The mixture was stirred under a nitrogen atmosphere for 16 hours before diluting with EtOAc. The organic phase was washed with 2M HCl, followed by brine, dried over MgSO4 and evaporated to dryness. The crude acyl sulphonamide was purified on silica to yield N-{1-[5-chloro-2-(4-methoxy-benzyloxy)-benzyl]-5-methyl-1H-pyrazole-3-carbonyl}-benzenesulfonamide, 16.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH:13]C(=O)C(C)(C)C)=[N:11][CH:12]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>>[CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)Nc1ccc(COCC2CC2)cn1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(COCC2CC2)cn1

Procedure:
This material was prepared in analogy to example 86 step B] from N-(5-cyclopropylmethoxymethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.87 g) and 3M aqueous NaOH (5.54 mL) as a yellow solid (0.527 g). MS (ESI): 179.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH:16]([C:18]([O:20]C)=[O:19])[CH2:15][CH2:14][N:13]1[C:22]([O:24][CH3:25])=[O:23].[Br-].[Li+].C(N(CC)CC)C>C(#N)C.O>[CH3:25][O:24][C:22]([N:13]1[CH2:14][CH2:15][CH:16]([C:18]([OH:20])=[O:19])[CH2:17][CH:12]1[C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:7][C:2]=1[CH3:1])=[O:23]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)cc2C)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(C(F)(F)F)cc1C
Yield: 91.1 %

Procedure:
Dimethyl 2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1,4-dicarboxylate (8.9 g, 24.77 mmol) was dissolved in acetonitrile (80 mL). Water (1.6 mL), lithium bromide (17.21 g, 198.14 mmol), and triethylamine (13.73 mL, 99.07 mmol) were added. The mixture was heated at reflux for 2.5 h. After cooling it was diluted with water and extracted with EtOAc twice and the combined organic layer washed with water. The combined aqueous layer was acidified with 2 M HCl and extracted three times with EtOAc. The combined organic layer was dried over Na2SO4, filtered and evaporated to give crude 1-(methoxycarbonyl)-2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (7.79 g, 91%). MS m/z 344 (M−H)−
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=3[O:15][CH2:16][C:17](O)=[O:18])[N:10]([C:24](=[O:34])[C:25]3[C:30]([F:31])=[CH:29][C:28]([F:32])=[CH:27][C:26]=3[F:33])[N:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:68][C:69]1[O:73][N:72]=[C:71]([NH2:74])[CH:70]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=3[O:15][CH2:16][C:17]([NH:74][C:71]3[CH:70]=[C:69]([CH3:68])[O:73][N:72]=3)=[O:18])[N:10]([C:24](=[O:34])[C:25]3[C:30]([F:31])=[CH:29][C:28]([F:32])=[CH:27][C:26]=3[F:33])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Reactant: Cc1cc(N)no1
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: Cc1cc(NC(=O)COc2ccccc2C2SC(c3ccc(F)cc3)=NN2C(=O)c2c(F)cc(F)cc2F)no1
Reaction time: 12 h

Procedure:
To a solution of {2-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-acetic acid (0.031 mmol) in DMF (1 mL) is added DIEA (0.058 mmol), HATU (0.058 mmol) and 5-methyl-isoxazol-3-ylamine (0.058 mmol). The reaction mixture is stirred for 12 hours. The mixture is purified by preparative LC/MS (20-100% MeCN/H2O) to give 2-{2-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-N-(5-methyl-isoxazol-3-yl)-acetamide: 1H NMR (400 MHz, CDCl3) δ 7.55-7.51 (m, 3H), 7.35-7.26 (m, 2H), 7.05-6.96 (m, 3H), 6.85 (d, J=8 Hz, 1H), 6.69 (t, J=7.6 Hz, 2H), 6.56 (s, 1H), 4.72 (s, 2H), 2.33 (s, 3H); LC/MS (ES+): 571.1 (M+1)+.