Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[S:9](=O)(=[O:12])([OH:11])[OH:10].C(=O)([O-])[O-].[Ba+2]>>[OH:2][C:1]1[CH:8]=[C:7]([S:9]([OH:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: O=S(=O)(O)O
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Product: O=S(=O)(O)c1ccc(O)c(O)c1
Temperature: 45 °C

Procedure:
Catechol (180 g.) was added in portions to stirred sulfuric acid (138.5 ml.) so that the reaction temperature remained below 25° C. After addition was complete, the semi-solid mixture was heated at 45° C. for 60 minutes then cooled to room temperature and poured into ice-water (700 ml.). The solution was neutralized with solid barium carbonate, the barium sulfate collected, the filtrate acidified to pH 1 with concentrated sulfuric acid then refiltered. The filtrate was evaporated to leave crude 3,4-dihydroxybenzenesulfonic acid (182.40 g.) which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:22][C:23]1[S:27][C:26]([CH2:28][CH2:29][CH:30]=O)=[CH:25][CH:24]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH:29]([CH2:28][C:26]4[S:27][C:23]([Cl:22])=[CH:24][CH:25]=4)[CH3:30])[C@@H:15]([CH2:19][CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CCC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Reactant: O=CCCc1ccc(Cl)s1
Product: CC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(C)Cc1ccc(Cl)s1

Procedure:
The title compound is prepared as described in EXAMPLE 278 using 1-(4-aminoquinazoline-7-ylmethyl)-3-ethyl-piperazine-2-one, EXAMPLE 77 and 3-(5-chloro-thiophen-2-yl)-propionaldehyde, EXAMPLE 28. 1H NMR (d6-DMSO+1 drop TFA, 300 MHz) δ9.80 (bs, 2H), 8.79 (s, 1H), 8.32 (d, 1H), 7.58 (m, 2H), 6.88 (d, 1H), 6.70 (d, 1H), 4.72 (AB, 2H), 4.00 (m, 1H), 3.72 (m, 1H), 3.48 (m, 2H), 3.23 (m, 3H), 2.72 (m, 2H), 1.96 (m, 4H), 0.98 (m, 3H). MS (ion spray), m/z, (M+H)=444, 446 (Cl pattern).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:25]#[N:26].[Na+].O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11][C:25]#[N:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: ClCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
The above obtained crude 2,4-dibenzyloxybenzyl chloride [VII] was dissolved in dimethyl sulfoxide (150 ml) and then thereto was added sodium cyanide (4 g), followed by stirring for 2 hours at room temperature (20° C.). The reaction mixture was added to water (1 liter) and extracted with dichloromethane (1 liter). The dichloromethane extract was concentrated under reduced pressure and the residue was purified by a silica gel column (inner diameter: 10 cm, length 50 cm; developer: dichloromethane-hexane 1:1 (v/v) mixed solution) and furthermore, was recrystallized from diethyl ether-hexane 2:1 (v/v) mixed solution to obtain 2,4-dibenzyloxyphenylacetonitrile [VIII] (14.3 g, yield from [VI]: 70%). Melting point: 99°-100° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:18]=O)=[C:4]([CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:27][C:28](=[O:30])[CH3:29])C=CC=CC=1>C1(C)C=CC=CC=1>[CH:18]([C:3]1[C:2]([CH3:1])=[C:7]([O:8][CH3:9])[C:6]([CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:27][C:28](=[O:30])[CH3:29]
Reactant: COC(=O)CCCc1cc(C)c(OC)c(C)c1C=O
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)CCCc1cc(C)c(OC)c(C)c1C=CC(C)=O

Procedure:
Methyl 4-(3,5-dimethyl-2-formyl-4-methoxyphenyl)butyrate (9.4 g) and 1-triphenylphosphoranylidene-2-propanone (21 g equiv) were heated and stirred at reflux in toluene for 48 hr. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica with dichloromethane elution to give methyl 4-[2-(but-1-en-3-one-1-yl)-3,5-dimethyl-4-methoxyphenyl]butyrate as a pale yellow oil. Pmr spectrum (CDCl3 ; δ in ppm): 1.83-2.69 (6H,m); 2.25 (3H,s); 2.28 (3H,s); 2.41 (3H,s); 3.66 (3H,s); 3.70 (3H,s); 6.26 (1H,d); 6.89 (1H,s); 7.65 (1H,d).
Reaction SMILES: [NH3:1].[N:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([CH3:16])[CH:12]=2)=[C:7]([O:17][CH3:18])[CH:6]=1)=[C:3]=[S:4]>CO>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([NH:2][C:3]([NH2:1])=[S:4])[CH:10]=[CH:9][C:8]=1[C:11]1[O:15][N:14]=[C:13]([CH3:16])[CH:12]=1
Reactant: COc1cc(N=C=S)ccc1-c1cc(C)no1
Reactant: N
Solvent: CO
Product: COc1cc(NC(N)=S)ccc1-c1cc(C)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
Step H (4): Methanolic ammonia (1.3 mL, 9.28 mmol) was added to a flask charged with 5-(4-isothiocyanato-2-methoxyphenyl)-3-methylisoxazole (508 mg, 2.063 mmol) in MeOH (4.6 mL). After stirring at rt for 24 h, the reaction mixture was concentrated to dryness in vacuo to afford 1-(3-methoxy-4-(3-methylisoxazol-5-yl)phenyl)thiourea (540 mg, 2.051 mmol, 99% yield). LC-MS (M+H)+ 264.2. 1H NMR (400 MHz, methanol-d4) δ ppm 7.82 (d, J=8.56 Hz, 1 H) 7.49-7.54 (m, 1 H) 6.99 (dd, J=8.56, 2.01 Hz, 1 H) 6.67 (s, 1 H) 3.96 (s, 3 H) 2.30 (s, 3 H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[C:18]2[CH2:19][C:20]([CH3:27])([CH3:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH2:23]2)[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(C#N)cc2)cc1
Agent: BrB(Br)Br
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(C#N)cc2)CC(C)(C)C1
Yield: 52 %

Procedure:
The demethylation protocol described for 208 was used. 4-[[4-(methyloxy)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]benzonitrile (209) (0.700 g, 1.95 mmol) was treated with BBr3 to afford 0.350 g (52%) of compound 210 as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.58 (d, J=8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 7.02.(d, J=8.4 Hz, 2H), 6.79 (d, J=8.7 Hz, 2H), 2.01 (s, 2H), 1.94 (s, 2H), 1.33 (s, 2H), 0.96 (s, 6H), 0.95 (s, 6H). LCMS (ESI): m/z 344 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:16][CH2:15][CH:14]([CH:17](O)[CH3:18])[CH2:13][CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.CCN(CC)CC.[CH:27]([Si:30]([O:37]S(C(F)(F)F)(=O)=O)([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][O:37][Si:30]([CH:31]([CH3:33])[CH3:32])([CH:34]([CH3:36])[CH3:35])[CH:27]([CH3:28])[CH3:29])[CH2:13][CH2:12]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CC(O)C1CCN(c2nnc3ccc(F)cn23)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](OCCC1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.4 %

Procedure:
To a solution of Intermediate 66a (319 mg, 1.21 mmol) and Et3N (252 μL, 1.82 mmol) in DCM (10 mL) was added triisopropylsilyltrifluoromethane sulfonate (319 μL, 1.45 mmol) and the mixture stirred at RT for 1.5 h. The mixture was washed with sat. aq. NaHCO3 solution, dried and concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as an orange solid (465 mg, 92%). LCMS (Method 3): Rt 5.35 min, m/z 421 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.[Br:19]Br.C1(C)C=CC=CC=1>C(O)(=O)C>[Br:19][C:11]1[C:12]([C:13]#[N:14])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[NH:9][C:10]=1[C:15]([F:18])([F:16])[F:17]
Reactant: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Reactant: BrBr
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen purge, a suspension or 2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile(1.6 g7 0.005 mol) in acetic acid (25 mL) is heated, all the material dissolving to a clear solution at about 60° C. A solution of bromine (0.8 mL; 0.015 mol) in acetic acid (10 mL) is added dropwise over 15 minutes to the refluxing solution. The solution is refluxed 6 hours then allowed to stir 18 hours at room temperature. The HPLC of the reaction mixture shows about 80% conversion to product. The mixture is heated back to reflux and more bromine (0.5 mL; 0.01 mol) in acetic acid (5 mL) is added dropwise. After refluxing another 3 hours, the aliquot shows >95% conversion to product. The reaction is cooled, and solvent removed under reduced pressure on a rotary evaporator to obtain a dark grey solid. Toluene is added to the mixture and removed under reduced pressure, but the odor of acetic acid still remains. The entire material is dissolved in hot toluene (75 mL) to a turbid solution which is treated with DARCO filter and filtered. The light pink solution deposits a white solid upon cooling to ambient. After cooling in the freezer, the solid is collected by filtration, washed with hexanes, and dried on the filter. Further drying in a vacuum oven at 45° C. provides the product (1.2 g; app. 60% theoretical); mp 247°-250° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH:12](OCC)(OCC)OCC>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][CH:12]=[N:11][C:9](=[O:10])[C:3]=2[N:4]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)c1nc(Cl)ccc1N
Product: O=c1nc[nH]c2ccc(Cl)nc12
Temperature: 25 °C
Yield: 82 %

Procedure:
A suspension of 3-amino-6-chloropicolinamide (1.67 g, 9.74 mmol) in triethyl orthoformate (73.0 mL) was refluxed for 3 hours. The reaction mixture was cooled to room temperature, and then filtered. The filtercake was dried under vacuum to give 6-chloropyrido[3,2-d]pyrimidin-4(1H)-one (1.45 g, 82%) as a brown solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 7.66 (1H, d, J=8.4 Hz), 8.00 (1H, s), 8.03 (1H, d, J=1.2 Hz), 12.57 (1H, brs).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5](=[CH:7][CH2:8][CH2:9][CH:10]([CH2:12][CH:13]=[O:14])[CH3:11])[CH3:6].[Cl-].[NH4+]>CCOCC>[CH3:11][CH:10]([CH2:9][CH2:8][CH:7]=[C:5]([CH3:6])[CH3:4])[CH2:12][CH:13]([OH:14])[CH3:1]
Reactant: C[Mg]Br
Reactant: CC(C)=CCCC(C)CC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)=CCCC(C)CC(C)O

Procedure:
Eighty ml. of a 3M solution of methylmagnesium bromide in ether is added slowly to 31 g. of citronellal in 250 ml. of dry ether. The mixture is heated at reflux for about 1 hour, cooled to 0° and treated with saturated aqueous ammonium chloride until reaction subsides. The organic layer is separated and the aqueous layer extracted with ether. The organic layer and ether extracts are combined, washed with water and brine and dried over magnesium sulfate. Evaporation of the solvent gives 4,8-dimethylnon-7-en-2-ol.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:17][CH3:18])[CH2:4][NH:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[N:7]=1>CO.[Pd]>[CH3:18][O:17][CH:3]([O:2][CH3:1])[CH2:4][NH:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[N:7]=1
Reactant: COc1ccc([N+](=O)[O-])c(NCC(OC)OC)n1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N)c(NCC(OC)OC)n1

Procedure:
A solution of N-[2,2-bis(methyloxy)ethyl]-6-(methyloxy)-3-nitro-2-pyridinamine (2.5 g, 10 mmol) in methanol was hydrogenated at 50 psi for 0.5 h over 10% palladium on charcoal (0.9 g). The mixture was filtered, evaporated, and azeotroped with chloroform affording a dark oil (2.2 g).
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[C:6]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[N:15][N:16]([CH3:18])[CH:17]=2)[N:5]=1)[CH3:2].O.O.Cl[Sn]Cl>CCOC(C)=O>[CH2:1]([S:3][C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[C:6]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[N:15][N:16]([CH3:18])[CH:17]=2)[N:5]=1)[CH3:2]
Reactant: CCSc1nc(-c2cn(C)nc2-c2ccccc2F)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CCSc1nc(-c2cn(C)nc2-c2ccccc2F)ccc1N
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A solution of 2-(ethylthio)-6(3-(2-fluorophenyl)-1methyl-1H-pyrazol-4-yl)-3-nitropyridine (2.87 g, 8.01 mmol, 1.00 eq.) and SnCl2.2H2O (9.05 g, 40.1 mmol, 5.0 eq.) in EtOAc (200 mL) was refluxed for 2 h. After cooling to room temperature, the solution was washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated in vacuo to give 2-(ethylthio)-6-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)pyridine-3-amine as a yellow solid (2.31 g, 88% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][O:11]C(=O)C)[N:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CO>O>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(COC(C)=O)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1nc(CO)cs1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71 %

Procedure:
Mass (m/e): 214 (M30) . (2) A mixture of 2-acetylamino-4-acetoxymethylthiazole (72 g), potassium carbonate (23.2 g), methanol (1.1 l) and water (0.1 l) was stirred for 3 hours and 20 minutes at ambient temperature. An insoluble material was filtered off and the filtrate was neutralized with 2N hydrochloric acid and evaporated. To the residue was added a mixture of chloroform and methanol (100 ml, 1:1 V/V) and the mixture was heated. An insoluble material was filtered off and the filtrate was concentrated. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (10:1 V/V) to give 2-acetylamino-4-hydroxymethylthiazole (41.11 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)=[CH:3][CH:2]=1.[NH2:17][C@@H:18]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[CH:45][CH:44]=1)[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)=[O:20]>>[C:50]([O:49][C:46]1[CH:47]=[CH:48][C:43]([CH2:42][C@H:18]([NH:17][C:13](=[O:15])[CH2:12][O:11][NH:10][C:9]([NH:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:16])[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=2[N:31]=[CH:30][CH:29]=[CH:28]3)=[O:20])=[CH:44][CH:45]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: O=C(O)CONC(=O)NCc1ccncc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CONC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(pyridin-4-ylmethyl)ureidooxy)acetic acid (Compound VI-10) 67 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:25])[CH:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)(Cl)Cl>[C:26]([NH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:25])[CH:3]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1
Reaction time: 0.25 h

Procedure:
3 g of 1-(4-amino-2-chlorobenzoyl)-4-[2-(4-chlorophenyl)ethyl]-piperazine are stirred for 1 hour at room temperature in 30 ml of chloroform with 10 ml of acetic anhydride. The solution is concentrated by evaporation and water, 2N sodium hydroxide solution and 20 ml of ethyl acetate are added to the residue and the whole is stirred for 15 minutes. Filtering with suction and recrystallisation from ethanol/petroleum ether yield 1-[4-(N-acetylamino)-2-chlorobenzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine having a melting point of 158°-160°.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:18]N1C(=O)CCC1=O>C(#N)C>[Br:1][C:2]1[C:3]([O:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[C:4]([Cl:18])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cc(Oc2c(F)cccc2F)c(Br)cn1
Solvent: CC#N
Product: Nc1ncc(Br)c(Oc2c(F)cccc2F)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-bromo-4-(2,6-difluorophenoxy)pyridin-2-amine (301 mg, 1.0 mmol) and N-chlorosuccinimide (1.1 mmols) in acetonitrile (50 mL) is stirred at room temperature for one hour then heated at reflux for 24 hours. The reaction mixture is cooled and concentrated. The residue is purified via column chromatography to afford 5-bromo-3-chloro-4-(2,6-difluorophenoxy)pyridin-2-amine.
Reaction SMILES: O=C1[CH:6]([C:7](O)([OH:12])[C:8]([F:11])([F:10])[F:9])[CH2:5][CH2:4][O:3]1.Cl.C(O)(=O)C>O>[F:9][C:8]([F:11])([F:10])[C:7](=[O:12])[CH2:6][CH2:5][CH2:4][OH:3]
Reactant: O=C1OCCC1C(O)(O)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(CCCO)C(F)(F)F
Temperature: 125 °C
Yield: 125.1 %

Procedure:
A 500 mL three neck round bottom flask, fitted with reflux condenser, heating mantle, and magnetic stirrer was charged with 61.5 g(0.31 M) of 2,3,4,5-tetrahydro-2-oxo-3-(2,2,2-trifluoro-1,1-dihyroxyethyl)furan, 6.4 mL of concentrated HCl, 10 mL of water, and 80 mL of acetic acid. The reaction mixture was heated at 125° C. overnight. An additional 3.0 mL of concentrated HCl and 5.0 mL of water was added and the reaction mixture was heated for an additional 10 hours. The reaction was partitioned between water and ethyl ether while the water layer was neutralized with solid sodium bicarbonate (100 g). The ether solution was washed with water (2×20 mL), dried (anhydrous MgSO4), and solvent removed under reduced pressure to give 60 g(45%) of a pale yellow oil. nmr(CDCl3)α-2.14m,4H), 4.03(m,1H), 4.20(m,1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[S:14][CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CCO>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][C:13]2[S:14][CH:15]=[CH:16][C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CCOC(=O)c1ccsc1N
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Solvent: CCO
Product: CCOC(=O)c1ccsc1Nc1ccc(F)cc1[N+](=O)[O-]

Procedure:
2,5-Difluoro-nitrobenzene and ethyl 2-amino-thiophene-3-carboxylate, m.p. 125° C. (EtOH).
Reaction SMILES: Cl[C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>O1CCOCC1>[N+:13]([C:12]1[C:2]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:3]([CH:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])([O-:15])=[O:14]
Reactant: CCOC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: C1CCNCC1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1N1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 2-chloro-3-nitro-5-trifluoromethylbenzoate (4.2 g; 1 eq.) in dioxane (40 ml) is added piperidine (3.9 ml; 2.1 eq.). After stirring for 18 hours at room temperature, the medium is poured into water (50 ml) and the product is extracted with ethyl ether. The organic phase is washed with water, dried and concentrated. 4.9 g of ethyl 3-nitro-2-piperid-1-yl-5-trifluoromethylbenzoate are obtained in the form of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([O:15][Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH2:13][NH2:14])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:23][C:24]([CH3:28])([CH3:27])[CH:25]=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([O:15][Si:16]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:21][CH3:22])[CH2:13][NH:14][CH2:23][C:24]([CH3:28])([CH3:27])[CH3:25])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC[Si](CC)(CC)OC(CN)c1c(Cl)cnc2ccccc12
Reactant: CC(C)(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC[Si](CC)(CC)OC(CNCC(C)(C)C)c1c(Cl)cnc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a yellow clear solution of 2-(3-chloroquinolin-4-yl)-2-((triethylsilyl)oxy)ethanamine (A275-6) (0.217 g, 0.644 mmol) in DCM (2.15 mL) was added trimethylacetaldehyde (0.077 mL, 0.71 mmol), AcOH (0.045 mL, 0.77 mmol), and NaBH(OAc)3 (0.205 g, 0.966 mmol). The yellow homogeneous mixture was stirred at room temperature. After 2 h, the mixture was quenched with water (20 mL) and neutralized with 0.5 M NaOH (10 mL) to pH ˜9.0. The reaction mixture was extracted with DCM (2×50 mL). The organic extract washed with saturated NaCl (1×50 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow syrup. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEP™ pre-packed silica gel column (40 g), eluting with a gradient of 0% to 20% EtOAc in hexane, and dried under high vacuum to give N-(2-(3-chloroquinolin-4-yl)-2-((triethylsilyl)oxy)ethyl)-2,2-dimethylpropan-1-amine (A275) as colorless syrup. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (1H, s), 8.75 (1H, d, J=7.2 Hz), 8.04 (1H, dd, J=8.4, 1.0 Hz), 7.77 (1H, ddd, J=8.4, 6.9, 1.4 Hz), 7.61-7.68 (1H, m), 5.70 (1H, dd, J=7.7, 5.0 Hz), 3.26 (1H, dd, J=12.6, 8.1 Hz), 2.85 (1H, dd, J=12.6, 5.0 Hz), 2.23-2.39 (2H, m), 1.72 (1H, br. s.), 0.81 (9H, s), 0.72-0.79 (9H, m), 0.36-0.56 (6H, m); LCMS (ESI) m/z 407.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][C:14]([CH2:20][CH2:21][O:22][CH3:23])([C:17](O)=[O:18])[CH2:13][CH2:12]1)(=[O:10])=[O:9].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:48]([O:50][C:51](=[O:60])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=1)[CH3:49].CN1CCOCC1>C1COCC1>[CH2:48]([O:50][C:51](=[O:60])[CH2:52][C:53]1[CH:54]=[CH:55][C:56]([NH:59][C:17]([C:14]2([CH2:20][CH2:21][O:22][CH3:23])[CH2:13][CH2:12][N:11]([S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:9])=[O:10])[CH2:16][CH2:15]2)=[O:18])=[CH:57][CH:58]=1)[CH3:49]
Reactant: COCCC1(C(=O)O)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(NC(=O)C2(CCOC)CCN(S(=O)(=O)c3ccccc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.6 %

Procedure:
1-(2-Chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid (2.82 g) were dissolved in THF (30 ml) under an argon atmosphere at RT and then sequentially treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (3.26 g), (4-amino-phenyl)-acetic acid ethyl ester (1.536 g) and N-methyl morpholine (1.04 ml). The reaction mixture was stirred 12 h at RT, and 1 h at reflux to complete the reaction. The mixture was partitioned between AcOEt and 1N HCl/water, the layers were separated; the organic layer was dried over sodium sulphate and then removed in vacuo. The residue was purified by chromatography on silica gel (CH2Cl2/AcOEt, 19/1 to 9/1) to give the desired (4-{[1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carbonyl]-amino}-phenyl)-acetic acid ethyl ester (2.47 g) which was directly used in the next step.