Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:32])[CH2:4][NH:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30].N1C=CC=CC=1.[S:39](Cl)(Cl)=[O:40].Cl>ClCCl>[Cl:28][C:26]1[CH:27]=[C:22]([C:16]2([C:18]([F:20])([F:21])[F:19])[O:15][N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]([NH:5][CH2:4][CH:3]4[O:32][S:39](=[O:40])[NH:1][CH2:2]4)=[O:31])=[C:8]([CH3:30])[CH:9]=3)[CH2:17]2)[CH:23]=[C:24]([Cl:29])[CH:25]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(O)CN
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC1CNS(=O)O1
Reaction time: 4 h

Procedure:
A solution of N-(3-amino-2-hydroxy-propyl)-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzamide (0.2 g) in dichloromethane (10 ml) was cooled to 0° C., treated with pyridine (0.32 ml) and thionyl chloride (0.06 ml), and stirred for 4 hours. The mixture was diluted with dichloromethane (50 ml), neutralized with 2N hydrochloric acid, and washed with water (50 ml). The organic layer was separated, dried over sodium sulfate and concentrated. Purification by chromatography on silica gel (eluent hexane/ethyl acetate 40:60) gave the title compound (20 mg). LCMS (Method G) 3.88 min, (M−H)− 534. 1HNMR (CDCl3, 400 MHz): 7.45-7.52 (m, 6H), 6.50 (m, 1H), 4.05 (d, 1H), 3.98 (m, 1H), 3.72 (d, 1H), 3.62 (m, 1H), 3.51 (m, 3H), 2.46 (s, 3H).
Reaction SMILES: [NH3:1].[CH3:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:35])[NH:11][CH:12]([C:18]([N:20]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[CH2:13][C:14]([O:16]C)=O)[CH:6]=[CH:7][CH:8]=1>CO>[CH3:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:35])[NH:11][CH:12]([CH2:13][C:14]([NH2:1])=[O:16])[C:18]([N:20]([CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CC(NC(=O)Nc1cccc(C)c1)C(=O)N(CC(=O)OC(C)(C)C)c1ccccc1
Reactant: N
Solvent: CO
Product: Cc1cccc(NC(=O)NC(CC(N)=O)C(=O)N(CC(=O)OC(C)(C)C)c2ccccc2)c1

Procedure:
A stream of ammonia is passed for 11 hours at a temperature in the region of 25° C. into a solution of methyl (RS)-3-[3-(3-methylphenyl)ureido]-N-(tertbutoxycarbonylmethyl)-N-phenylsuccinamate (4.7 g) in methanol (150 cc). The solution is then outgassed with a stream of nitrogen and concentrated under vacuum (2.7 kPa) at 60° C. The residue is crystallised in diethyl ether and the solid extracted with dichloromethane (40 cc). The solution thereby obtained is purified by chromatography on silica (0.063-0.200 mm) (25 g) contained in a column 1.6 cm in diameter [eluent: methylene chloride (1100 cc), then methylene chloride/methanol (98.5:1.5 by volume)], collecting 15-cc fractions. Fractions 80 to 127 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 60° C. After crystallisation in petroleum ether, (RS)-2-[3-(3-methylphenyl)ureido]-N-(tert-butoxycarbonylmethyl)-N-phenylsuccinamide (1.1 g), m.p. 192° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[C:41]([NH:44][C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)(=[O:43])[CH3:42]>C1(C)C=CC=CC=1.C(O)C>[C:41]([NH:44][C:45]1[CH:50]=[C:49]([C:13]2[N:12]=[C:11]3[N:17]([C:18]4[CH:19]=[CH:20][C:21]([C:24]5([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:27][CH2:26][CH2:25]5)=[CH:22][CH:23]=4)[C:8]([C:7]4[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=4)=[N:9][C:10]3=[CH:15][CH:14]=2)[CH:48]=[CH:47][CH:46]=1)(=[O:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2ccc3nc(-c4cccnc4N)n(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c3n2)c1
Temperature: 100 °C

Procedure:
To a suspension of tert-butyl (1-(4-(2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutyl)carbamate (3.0 g) in toluene (100 mL) and ethanol (100 mL) was added saturated aqueous sodium bicarbonate (15 ml) and (3-acetamidophenyl) boronic acid (2.18 g). The reaction was degassed for 5 minutes and Pd(PPh3)4 (0.300 g) was added. The reaction was again degassed for 5 minutes with nitrogen and then heated to 100° C. overnight. The reaction mixture was cooled to room temperature, dichloromethane (250 ml) and water (100 ml) were added to the reaction. The organics were separated, the aqueous washed with dichloromethane (1×100 ml) and the organics combined. The organics were washed with saturated sodium bicarbonate (1×100 ml) and brine (1×100 ml). The organics were dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (0-10% methanol in dichloromethane) gave the product as a brown solid with some co-eluting impurities. The fractions with the product were combined and concentrated to give a dark brown solid. The solid was triturated with ethyl acetate to give a tan solid (2.6 g, 70%). 400 M Hz 1H NMR (DMSO-d6) δ: 10.08 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.11 (bs, 1H), 7.99 (dd, J=5.2 Hz and 2.0 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.72-7.63 (m, 3H), 7.55-7.51 (m, 2H), 7.46-7.42 (m, 6H), 7.39-7.34 (m, 1H), 7.14-7.06 (m, 1H), 7.02 (s, 2H), 6.32 (dd, J=7.6 Hz and 4.8 Hz 1H), 2.48-2.40 (m, 4H), 2.07-1.98 (m, 4H), 1.89-1.79 (m, 1H), 1.38-1.12 (m, 9H); LCMS: 590 [M+H].
Reaction SMILES: [Br:1][C:2]1[C:3]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][C:27]([O:29][CH2:30][CH2:31]Cl)=[CH:28][C:22]=3[CH:21]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[I-].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:3]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][C:27]([O:29][CH2:30][CH2:31][N:37]4[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]4)=[CH:28][C:22]=3[CH:21]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc3cc(OCCCl)ccc3s2)n1
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(CCOc2ccc3sc(-c4nc(NCCN5C(=O)NC(=O)C5(C)C)ncc4Br)cc3c2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
1-(2-{5-Bromo-4-[5-(2-chloroethoxy)benzo[b]thiophen-2-yl]pyrimidin-2-ylamino}ethyl)-5,5-dimethylimidazolidine-2,4-dione (0.15 g, 0.27 mmol) was dissolved in DMF (2 mL) and treated with N-methylpiperazine (0.061 mL, 0.55 mmol) and catalytic amount of sodium iodide (0.025 g). The mixture was heated to 70° C. and stirred overnight. The reaction was cooled down to room temperature and poured into a saturated aqueous solution of sodium bicarbonate (15 mL). The resulting precipitate was collected by filtration, dissolved in DMF (2 mL) and purified by preparative HPLC. The clean fractions were treated with 2 M ammonia in methanol and the organic volatiles removed to give a suspension of a white solid in the aqueous layer, which was collected by filtration, washed well with water and dried overnight in a vacuum oven at 60° C. Yield=0.062 g. MS (M+H)+ 603/605.
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=O.[NH2:15][C@H:16]([CH:19]([CH3:21])[CH3:20])[CH2:17][OH:18]>C(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C@@H:16](/[N:15]=[CH:13]/[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=1)[CH2:17][OH:18]
Reactant: CC(C)[C@@H](N)CO
Reactant: O=Cc1ccccn1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)[C@H](CO)/N=C/c1ccccn1
Reaction time: 2 h
Yield: 100 %

Procedure:
Anhydrous MgSO4 (50 g, 415 mmol, 4.15 eq) and a substituted aryl or heteroaryl carboxaldehyde, e.g. 2-pyridinecarboxaldehyde (9.5 ml, 100 mmol, 1 eq), were added to a solution of (R)-(−)-2-amino-3-methyl-1-butanol (10.32 g, 100 mmol) in dry DCM (150 ml) at 0° C. The reaction was followed by LC/MS. The mixture was stirred at this temperature for 2 h 25. MgSO4 was filtered off and the DCM removed by evaporation to give the desired product (XVIII*), e.g. (2R)-3-methyl-2-{[(E)-2-pyridinylmethylidene]amino}-1-butanol as a yellowish oil (19.23 g, quantitative yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:18])[C:12]3[CH2:13][NH:14][CH2:15][CH2:16][C:11]=3[C:10](=[O:17])[O:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:19]([N:26]=[C:27]=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH2:19]([NH:26][C:27]([N:14]1[CH2:15][CH2:16][C:11]2[C:10](=[O:17])[O:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=3)([CH3:18])[C:12]=2[CH2:13]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC1(c2cccc(O)c2)OC(=O)C2=C1CNCC2
Solvent: ClCCl
Product: CC1(c2cccc(O)c2)OC(=O)C2=C1CN(C(=O)NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A mixture of 3-(3-hydroxyphenyl)-3-methyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (75 mg, 0.31 mmol) and benzyl isocyanate (48 μL, 0.40 mmol) in dichloromethane (5 mL) was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (68 mg, 58.8%). 1H NMR (300 Hz, CDCl3) δ 1.82 (s, 3H), 2.39 (br s, 2H), 3.30-3.40 (m, 1H), 3.42-3.55 (m, 1H), 3.94 (d, J=18.0, 1H), 4.25-4.40 (m, 3H), 4.97 (t, J=6.0, 1H), 6.77-6.84 (m, 2H), 7.15-7.38 (m, 7H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:13]\[C:14]3[CH:19]=[CH:18][C:17]([S:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([S:20][C:21]([F:24])([F:22])[F:23])=[CH:16][CH:15]=3)[C:9]2=[O:12])=[CH:5][C:4]=1[N:25]1[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1ccc(SC(F)(F)F)cc1)C2=O
Reaction time: 6 h

Procedure:
Compound 73 (1.0 g, 2.296 mmol) was dissolved in methanol 250 mL, Pd/C 400 mg was added, and the reaction was stirred under hydrogen balloon for 6 h. The result was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude compound 74, which was purified by flash chromatography using 100-200 mesh silica gel. The compound was eluted at 30% ethyl acetate in hexane as half white coloured solid 6-methoxy-5-morpholino-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one 74. 1HNMR (400 MHz, CDCl3) δ ppm 7.56 (d, 2H), 7.28 (d, 2H), 7.18 (s, 1H), 6.81 (s, 1H), 3.89 (m, 3H), 3.87 (m, 4H), 3.37 (dd, 1H), 3.15 (m, 4H), 3.06 (m, 1H), 2.96 (m, 1H), 2.66 (m, 2H); MS (ESI) m/z 438.0 (M+H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([NH:16][S:17](Cl)(=[O:19])=[O:18])=[O:15])[CH3:3].[CH2:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C1COCC1>[CH2:21]([O:27][S:17](=[O:18])(=[O:19])[NH:16][C:14]([NH:13][C:5]1[C:6]([CH:10]([CH3:11])[CH3:12])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:2]([CH3:3])[CH3:1])=[O:15])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCO
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)NS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCOS(=O)(=O)NC(=O)Nc1c(C(C)C)cccc1C(C)C
Reaction time: 16 h
Yield: 25.8 %

Procedure:
A solution of [[[2,6-bis(1 methylethyl)phenyl]amino]carbonyl]sulfamoyl chloride (5.0 g, 15.7 mmoles) in 80 mL THF was added dropwise to a solution of n-hexanol (1.60 g, 15.7 mmoles) and excess triethylamine (~3 mL) in 150 mL THF at room temperature under an atmosphere of N2. This was stirred for 16 hours and then concentrated in vacuo. The residue was partitioned between IN HCl and EtOAc and the organic layer was dried with MgSO4, filtered, and evaporated to give an oily tan solid. Trituration with acetone/hexanes (9:1) gave 1.56 g of the title compound as a white solid, mp 148-151° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[CH3:13]O>>[CH3:13][O:4][C@:3]1([CH2:2][OH:1])[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@@H:5]1[OH:6]
Reactant: CO
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CO[C@]1(CO)O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 160 °C
Reaction time: 0.03 h

Procedure:
A mixture of methanol and fructose was initially charged in a stirred vessel A. The fraction of fructose was 30% of the methanol fraction. The mixture was conveyed by a suitable pump B at a pressure of 120 bar continuously through the reactor C. The tubular reactor C was heated to a temperature of 160° C. by the heater D. A carrier stream comprising pure methanol from the reservoir F was heated to approx. 300° using the preheater G. At the mixing point H, the carrier stream was mixed with the reactant stream and fed to the reactor. The preheating temperature was sufficiently high that reaction temperature was already present at the mixing point, so that the temperature gradient in the reactor was sufficiently low to prevent carbonization at the wall. The residence time in the tubular reactor was approx. 2 min. With the aid of the control valve E, the pressure was kept at the target value mentioned. At the outlet of the system, the reacted product mixture was collected. According to HPLC, the product mixture contained 4% product.
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([N:16]=[CH:17][C:18]([S:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]3)=[N:19]2)=[CH:14][CH:13]=1>C(#N)C>[CH3:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([N:16]=[CH:17][C:18]([S:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([NH:31][CH2:2][CH2:3][S:4][C:5]4[S:6][CH:7]=[CH:8][CH:9]=4)[CH2:29][CH2:30]3)=[N:19]2)=[CH:14][CH:13]=1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Reactant: BrCCSc1cccs1
Solvent: CC#N
Product: COc1ccc2ncc(SCCN3CCC(NCCSc4cccs4)CC3)nc2c1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
2-(2-Bromo-ethylsulfanyl)-thiophene (51 mg, 0.22 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70 mg, 0.22 mmol, 1.0 eq) in acetonitrile (5 mL). After 15 hours stirring at 90° C. the reaction mixture is concentrated to give a residue that is purified by preparative HPLC to afford {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-[2-(thiophen-2-ylsulfanyl)-ethyl]-amine as a brown waxy solid (19 mg, 20% yield).
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:21][C:22]([NH2:24])=[S:23].C([O-])(=O)C.[Na+].O>C(O)C>[NH2:24][C:22]1[S:23][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:21]=1
Reactant: CCOC(=O)C(=NOCc1ccc(Cl)cc1)C(=O)CCl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NOCc1ccc(Cl)cc1)c1csc(N)n1
Yield: 32.4 %

Procedure:
Ethyl 4-chloro-2-(4-chlorobenzyloxyimino)-3-oxobutyrate (syn isomer, 37.2 g.), thiourea (9.82 g.), sodium acetate 3 hydrate (17.55 g.), water (80 ml.) and ethanol (80 ml.) were treated in similar manner to that of Example P-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-(4-chlorobenzyloxyimino)acetate (syn isomer, 12.86 g.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]([F:24])([F:23])[F:22])=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C>[Pt]=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:21]([F:24])([F:22])[F:23])=[C:4]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(Cl)c2C(F)(F)F)CC1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(Cl)c2C(F)(F)F)CC1
Reaction time: 16 h
Yield: 26.1 %

Procedure:
A mixture of tert-butyl 4-(3-chloro-2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.438 g, 1.21 mmol), platinum oxide (0.082 g, 0.363 mmol), acetic acid (0.073 g, 1.21 mmol), and ethyl acetate (20 mL) was hydrogenated using a balloon for 20 h and filtered. The material was re-submitted to hydrogenation at 80° C. for 16 h and filtered. After concentration, the residue was chromatographed over silica gel (0-30% EtOAc in hexanes) to give tert-butyl 4-(3-chloro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate as colorless thick oil (0.115 g, 26%): 1H NMR (300 MHz, CDCl3) δ7.42-7.30 (m, 3H), 4.25 (br, 2H), 3.21 (m, 1H), 2.81 (m, 2H), 1.80-1.60 (m, 4H), 1.49 (s, 9H); MS (ESI+) m/z 308 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10])=[CH:5][CH:4]=1.[C:11]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH:19]=[C:20]([CH2:28][C:29]2[CH:30]=[N:31][C:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:33][CH:34]=2)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:12]=1>>[C:11]1([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH:19]([S:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:20]([CH2:28][C:29]2[CH:30]=[N:31][C:32]([NH:35][C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])=[CH:33][CH:34]=2)[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=CCCc2cccc(-c3ccccc3)c2)C(=O)OC(C)(C)C)cn1
Reactant: COc1ccc(CS)cc1
Product: COc1ccc(CSC(CCc2cccc(-c3ccccc3)c2)C(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)cc1
Yield: 89.9 %

Procedure:
A solution of 4-methoxy-α-toluenethiol (0.58 mL, 4.17 mmol) in dry, degassed DMF (2 mL) was treated at room temperature with a catalytic amount of sodium hydride (60% in mineral oil), followed by a solution of tert-butyl 5-(1,1′-biphenyl-3-yl)-2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)pent-2-enoate (1.073 g, 2.08 mmol) in dry, degassed DMF (5 mL). After 20 h at room temperature the reaction mixture was diluted with EtOAc and washed with water three times. The organic layer was dried Na2SO4), concentrated, and subjected to flash chromatography (heptan/EtOAc, 3:1 and toluene/EtOAc 12:1) to give tert-butyl 5-(1,1′-biphenyl-3-yl)-2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-3-[(4-methoxybenzyl)thio]pentanoate (1.251 g, 90%)
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]([OH:19])=O)=[CH:14][C:13]=3[CH:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][NH2:34])=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][NH:34][C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:20][C:13]=3[CH:14]=2)=[O:19])=[CH:29][CH:30]=1
Reactant: O=C(O)c1cc2cc(OCCN3CCCC3)ccc2o1
Reactant: COC(=O)c1ccc(OCCN)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCNC(=O)c2cc3cc(OCCN4CCCC4)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
To a solution of 5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carboxylic acid (156 mg, 0.50 mmol) and 4-(2-aminoethoxyl)benzoic acid methyl ester hydrochloride (129 mg, 0.56 mmol) in DMF (4.5 ml) in a 20 ml vial was added diisopropylethylamine (0.88 ml, 5.1 mmol). A solution of 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (740 μL, 0.82 M, 0.61 mmol) in DMF was added to give a bright yellow solution. The vial was purged with nitrogen and stirred at room temperature for 18 h. The solution was removed and the residue was dissolved in EtOAc (25 ml) and washed with H2O, 1.0M aqueous K2CO3, and brine. The organic layer was dried over anhydrous MgSO4 and solvent was removed on a rotary evaporator. Purification of the residue by column chromatography on a silica gel column using 93:5:2 CH2Cl2:MeOH:TEA eluent provided 4-{2-[5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carbonylamino]-ethoxy}-benzoic acid methyl ester as a beige solid (174 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[C:7](=[CH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:6]2.ClC1C=CC=C(C(OO)=[O:30])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[C:7](=[CH:15][C:16]1[CH:21]=[CH:20][N+:19]([O-:30])=[CH:18][CH:17]=1)[CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)C(=Cc1ccncc1)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(=O)C(=Cc1cc[n+]([O-])cc1)C2
Reaction time: 4 h
Yield: 94.6 %

Procedure:
4-[(5,6-Dimethoxy-1-indanon-2-ylidene)methyl]pyridine (2.5 g) was dissolved in methylene chloride (60 ml) and chilled. m-Chloroperbenzoic acid (2.0 g) was added to reaction mixture and then stirred for 4 hours. Solid obtained was filtered. The wet solid so obtained was stirred with 10% sodium bicarbonate solution. The solid was filtered, washed with acetone and then dried to get the title compound (2.5 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])#[CH:17]>C(Cl)Cl.C(O)(C)C>[C:16]([C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:22]=[CH:23][CH:24]=1)#[CH:17]
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Reactant: C#Cc1cccc(N)c1
Solvent: ClCCl
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3cc(F)c([N+](=O)[O-])cc23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
4-chloro-7-fluoro-6-nitroquinazoline (12 g, 0.052 mol) was dissolved in 120 ml DCM. A solution of 3-ethynylaniline (7 g, 0.057 mol) in 200 ml isopropanol was added dropwise in an ice bath. The solution was stirred for 1 hour in the ice bath, then TEA (7 g, 0.069 mol) was added and allowed to stir for another 0.5 hour at room temperature. Yellow precipitate was formed and the solid was filtered and washed with 20 ml isopropanol twice, dried to give N-(3-ethynylphenyl)-7-fluoro-6-nitroquinazolin-4-amine 8.2 g as a yellow solid (50.3% yield).