Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]4([C:28]([O:30][CH3:31])=[O:29])[CH2:27][CH2:26][CH2:25]4)[CH2:14][C:13](=O)[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:43]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]4([C:28]([O:30][CH3:31])=[O:29])[CH2:27][CH2:26][CH2:25]4)[CH2:14][C:13](=[S:43])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C1(Oc2ccc(Cl)cc2C2CC(=O)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CCC1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C1(Oc2ccc(Cl)cc2C2CC(=S)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg, 0.05 mmol) and P2S5 (44 mg, 0.2 mmol) in THF (1 mL) was stirred at room temperature overnight, and then diluted with toluene (10 mL). The mixture was concentrated in vacuo and the residue was washed with DCM twice. The DCM solution was collected and purified by flash chromatography to give the title compound as white solid (12 mg).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([N:13]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN([CH:36]=[O:37])C>>[CH2:26]([N:13]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[C:17]([CH:36]=[O:37])=[CH:16][CH:15]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc2cccc(N(Cc3ccccc3)Cc3ccccc3)c2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(C=O)ccc(N(Cc3ccccc3)Cc3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of DMF (30 mL) was added POCl3 (10.65 mL, 116 mmol) over 30 minutes at 0° C. The mixture was then stirred at 0° C. for 30 minutes and added 4 (11.75 g, 33.2 mmol) in DMF (120 mL). The mixture was stirred at room temperature for six days and the poured into ice-water. The product mixture was extracted with dichloromethane and the organic layer washed with water, aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated to afford 13.58 g of 4-(dibenzylamino)-6-methoxy-1-naphthaldehyde (5) which was used in next step without further purification.
Reaction SMILES: C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[CH2:28]([O:31][C:32]([N:34]1[C@H:38]([C:39]([N:41]([CH2:43][C:44]2[N:45]3[C:51]([CH2:52][NH:53][C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])=[N:50][CH:49]=[C:46]3[S:47][CH:48]=2)[CH3:42])=[O:40])[CH2:37][C@H:36]([S:60][C:61]2[C@H:62]([CH3:85])[C@@H:63]3[C@@H:73]([C@H:74]([O:76][Si](C(C)(C)C)(C)C)[CH3:75])[C:72](=[O:84])[N:64]3[C:65]=2[C:66]([O:68][CH2:69][CH:70]=[CH2:71])=[O:67])[CH2:35]1)=[O:33])[CH:29]=[CH2:30].P([O-])([O-])([O-])=O>C1COCC1>[CH2:28]([O:31][C:32]([N:34]1[C@H:38]([C:39]([N:41]([CH2:43][C:44]2[N:45]3[C:51]([CH2:52][NH:53][C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])=[N:50][CH:49]=[C:46]3[S:47][CH:48]=2)[CH3:42])=[O:40])[CH2:37][C@H:36]([S:60][C:61]2[C@H:62]([CH3:85])[C@@H:63]3[C@@H:73]([C@H:74]([OH:76])[CH3:75])[C:72](=[O:84])[N:64]3[C:65]=2[C:66]([O:68][CH2:69][CH:70]=[CH2:71])=[O:67])[CH2:35]1)=[O:33])[CH:29]=[CH2:30]
Reactant: C=CCOC(=O)NCc1ncc2scc(CN(C)C(=O)[C@@H]3C[C@H](SC4=C(C(=O)OCC=C)N5C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]5[C@H]4C)CN3C(=O)OCC=C)n12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=CCOC(=O)NCc1ncc2scc(CN(C)C(=O)[C@@H]3C[C@H](SC4=C(C(=O)OCC=C)N5C(=O)[C@H]([C@@H](C)O)[C@H]5[C@H]4C)CN3C(=O)OCC=C)n12
Temperature: 25 °C
Reaction time: 27.5 h
Yield: 81.8 %

Procedure:
Acetic acid (0.30 ml) and 1.75 ml of a 1 M tetra-n-butylammonium fluoride/THF solution are added to a solution of 300 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[N-[5-(allyloxycarbonylaminomethyl)imidazo[5,1-b]thiazol-3-yl]methyl-N-methylaminocarbonyl]pyrrolidin-3-yl]thio-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-1-methylcarbapen-2-em-3-carboxylate in 5.2 ml of anhydrous THF, and the mixture is stirred in an argon atmosphere at room temperature for 27.5 hr. 1/15 M phosphate buffer (pH 7.0) (10 ml) is added thereto, and the mixture is extracted twice with 30 ml of ethyl acetate. The combined organic layers are dried over a 1:1 mixture of anhydrous magnesium sulfate and potassium carbonate and filtered, and the solvent is removed under reduced pressure and by filtrate to give a colorless viscous material. The viscous material is successively purified by column chromatography on silica gel (ethyl acetate:methanol=97:3 to 95:5) and on Sephadex LH-20 (chloroform:methanol=1:1) to give 212.6 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[N-[5-(allyloxycarbonylaminomethyl)imidazo[5,1-b]thiazol-3-yl]methyl-N-methylaminocarbonyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate as a colorless amorphous material.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32]>C(O)C.O.Cl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Yield: 52.4 %

Procedure:
A mixture of 2.00 g (0.0066 mole) of 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 1.655 g (0.0099 mole) of 4-amino-3-methoxybenzoic acid and 200 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then concentrated under reduced pressure. The solid was washed with water and then purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (92:8:0.3) to give 1.500 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-1).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([C:23](=[O:29])[N:24]([CH:26]([CH3:28])[CH3:27])[CH3:25])[CH:17]=2)=[C:10]([CH3:30])[CH:9]=1)=[O:6])C.S([O-])([O-])(=O)=O.[Mg+2].[NH3:38]>CCO.C(Cl)Cl>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:11]2[C:10]([CH3:30])=[CH:9][C:8]([NH:7][C:5]([C:4]([NH2:38])=[O:3])=[O:6])=[CH:13][C:12]=2[CH3:14])=[CH:17][C:18]=1[C:23](=[O:29])[N:24]([CH:26]([CH3:28])[CH3:27])[CH3:25]
Reactant: CCOC(=O)C(=O)Nc1cc(C)c(Oc2ccc(O)c(C(=O)N(C)C(C)C)c2)c(C)c1
Reactant: N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(NC(=O)C(N)=O)cc(C)c1Oc1ccc(O)c(C(=O)N(C)C(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-{4-[4-hydroxy-3-(isopropylmethylcarbamoyl)-phenoxy]-3,5-dimethyl-phenyl}-oxamic acid ethyl ester (7.1 mg, 0.017 mmol) in 1 mL of EtOH in the presence of magnesium sulfate (10 mg) at 0° C. was bubbled in NH3 gas for 10 min. The solution was allowed to warm to RT. After stirring at RT for 0.5 h, the solution was diluted with 2 mL of CH2Cl2 and filtered. The filtrate was concentrated to give the title compound as a white solid. MS Calc.: 399.5 Found: 398.4 (M−1).
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[CH3:2].[Cl:33]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:31]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[Cl:33])=[CH:15][CH:16]=1)[CH3:32]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCN(CC)CCCCCCOc1ccc(C(=Cc2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCCCCOc1ccc(C(=C(Cl)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
Combine (E and Z)-1-[4-(6-diethylaminohexoxy)phenyl]-1,2-diphenyl-ethylene (2.17 g, 5.07 mmol), N-chlorosuccinimide (0.745 g, 5.57 mmol), and chloroform (40 mL). Heat to reflux for 18 hours. Cool to ambient temperature. Add N-chlorosuccinimide (0.745 g, 5.57 mmol). Heat to reflux. After 2 hours evaporate in vacuo. Chromatograph on silica gel eluting with 10% methanol/dichloromethane. Combine product containing fractions and concentrate in vacuo to give the title compound. Separate the isomers by HPLC, 90 mg per injection, using a Waters and Associates μPorasil column (19 mm by 300 mm), eluting with 80/20/0.2 chloroform/hexane/triethylamine at 20 mL/minute to give (E)-1-[4-(6-diethylaminohexoxy)phenyl]-1,2-diphenyl-2-chloro-ethylene and (Z)-1-[4-(6-diethylaminohexoxy)phenyl]-1,2-diphenyl-2-chloro-ethylene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].C(=O)([O-])[O-].[K+].[K+].[OH:27][C:28]1[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][N:29]=1>CN(C)C=O.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:34][C:32]3[CH:31]=[CH:30][NH:29][C:28](=[O:27])[CH:33]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: Oc1ccnc(O)c1
Reactant: FC(F)(F)c1cc(Oc2ccc(CCl)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc[nH]1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A solution of 4-(chloromethyl)phenyl 4-chloro-3-(trifluoromethyl)phenyl ether (500, mg, 1.557 mmol), potassium carbonate (500 mg, 3.62 mmol) and 2,4-dihydroxypyridine (350 mg, 3.15 mmol) in N,N-dimethylformamide (DMF) (5 mL) was heated at 60° C. for overnight, then cooled to rt and diluted with acetonitrile. Solid suspension was removed by filtration, concentrated. Purification via Biotage-C18 system afforded the title product (310 mg) as a white solid. LC-MS (ESI): m/z 396 [M+H]+; 3.48 min (ret time).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:15]1([O:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:22](=[O:23])[O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(Br)nc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Br)nc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-5-aminopyridine (3.0 g, 17.3 mmol) in THF (44 mL) cooled to 0° C. was added pyridine (1.8 mL, 21.7 mmol) followed by phenylchloroformate (2.3 mL, 18.2 mmol). A precipitate formed and the reaction was stirred at 0° C. for 1 h. The reaction was stirred at RT overnight and quenched with 1N HCl. The mixture was extracted with EtOAc. The organic layer was washed with water, saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated to give the title compound as a biege solid (4.81 g, 94% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:25]3[CH2:26][CH2:27][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36])[CH2:29][CH2:30]3)=[O:22])[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 944.7 %

Procedure:
To 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1 eq, 200 mg, 0.52 mmol), tert-butyl 4-piperidinylcarbamate (1 eq, 105 mg, 0.052 mmol), and triethylamine (3 eq, 0.22 mL, 1.57 mmol) was added (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1 eq, 232 mg, 0.52 mmol). The reaction was stirred 16 h and then concentrated in vacuo. The crude material was purified by column chromatography 0-100% ethyl acetate/hexanes to yield 277 mg (93%) of desired product. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 11H) 1.95-2.10 (m, 2H) 2.14-2.25 (m, 3H) 2.97 (br. s., 1H) 3.25 (d, J=7.63 Hz, 1H) 3.66-3.82 (m, 1H) 4.31 (d, J=13.37 Hz, 1H) 4.49 (d, J=5.84 Hz, 1H) 4.66 (d, J=13.09 Hz, 1H) 7.03-7.10 (m, 2H) 7.12-7.18 (m, 1H) 7.21-7.34 (m, 3H) 7.45 (d, J=2.07 Hz, 1H); [M+Na]+ 587.4.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.N1C=CC=CC=1>ClCCl>[Br:13][C:9]1[N:8]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cccc(Br)n1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(Br)n1
Reaction time: 4 h
Yield: 75.2 %

Procedure:
Methanesulphonyl chloride (0.74 g) in dichloromethane (5 ml) was added over 2 min to a stirred solution of 2-amino-6-bromopyridine (1.1 g) and pyridine (0.57 g) in dichloromethane (5 ml). After 4 h, the solvent was evaporated in vacuo to give an oil which was purified by FCC eluting with System A (95:5:1) to give the title compound as a white solid (1.2 g), m.p. 90°-94° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:24][C:23]([F:25])([F:26])[C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][NH2:7])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reaction time: 5 h
Yield: 78.9 %

Procedure:
{2-[4-(3-Trifluoromethyl-phenoxy)-phenyl]ethyl}-carbamic acid tert-butyl ester (354 mg, 0.928 mmol, 1 eq) was dissolved in dry DCM (3 ml) under argon atmosphere and TFA (355 μl, 5 eq) was added. Reaction mixture was stirred for 5 h. In the reaction mixture was added more DCM (15 ml) and was extracted with saturated NaHCO3 (3×15 ml) and brine. Organic layer was dried over anhydrous Na2SO4, filtered and evaporated to give a product 2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (206 mg, yield=64.7%, purity=65%). [M+H]+=282.28 1H NMR (300 MHz; CDCl3) δ/ppm 2.76-2.80 (m, 2H), 2.93-3.04 (m, 2H), 6.92-6.98 (m, 2H), 7.02-7.35 (m, 5H), 7.37-7.45 (m, 1H)
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([NH:29][C:30](=[O:35])[CH2:31]C(O)=O)=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26].Cl>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:31]/[C:30]([NH:29][C:23]2[CH:22]=[CH:21][C:20]([Br:19])=[CH:28][C:24]=2[C:25]([OH:27])=[O:26])=[O:35])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)Nc1ccc(Br)cc1C(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1ccc(/C=C/C(=O)Nc2ccc(Br)cc2C(=O)O)cc1OC
Yield: 67.1 %

Procedure:
Piperidine (0.13 mL, 1.4 mmol) was added to a suspension of 3,4-dimethoxybenzaldehyde (0.22 g, 1.4 mmol) and 5-bromo-2-[(carboxyacetyl)amino]benzoic acid (0.34 g, 1.1 mmol) in toluene (4.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-2-[[3-(3,4-Dimethoxyphenyl)-1-oxo-2-propenyl]amino]-5-bromobenzoic acid (0.30 g, 66%) was obtained as a yellow crystalline solid; mp 210-213° C.; δH (400 MHz, DMSO-d6) 3.79 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 6.78 (d, J=15.6 Hz, 1H, CH═CHCO), 6.98 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.24 (d, J5′,6′=8.4 Hz, 1H, H6′), 7.36 (s, 1H, H2′), 7.56 (d, J=15.6 Hz, 1H, CH═CHCO), 7.78 (dd, J3,4=8.4, J4,6=2.0 Hz, 1H, H4), 8.06 (d, J4,6=2.0 Hz, 1H, H6), 8.62 (d, J3,4=8.4 Hz, 1H, H3), 11.30 (s, 1H, NH), 13.61 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 28.6, 55.5, 55.6, 110.4, 111.6, 114.0, 119.5, 122.5, 122.7, 127.1, 133.1, 136.4, 140.2, 142.0, 149.0, 150.7, 164.2, 168.1; HRMS (ESI) calculated for C13H16BrNO5 [M+Na]+ 428.0104. found 428.0105; vmax 1026, 1247, 1510, 1595, 1698, 2515, 2829, 3226, 3619 cm−1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:28].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:28])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
A solution of (R)-benzyl 3-(tert-butoxycarbonylamino)piperidine-1-carboxylate (5.00 g, 14.95 mmol) in dry DMF (50 mL) was added dropwise to a suspension of sodium hydride 60% in mineral oil (0.7176 g, 17.94 mmol) in dry DMF (10 mL). The mixture was stirred at 0° C. for 1 hour and allowed to stir at room temperature for 2 hours. Then the mixture was cooled to 0° C. and treated dropwise with iodomethane (1.024 mL, 16.45 mmol). The reaction mixture was stirred at 0° C. for 1 hour and allowed to warm to room temperature over 18 hours. Water (40 mL) was added, and the mixture was extracted into EtOAc (3×50 mL). The organic layers were combined, washed with water (3×20 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (Biotage Flash 40M+) eluting with 20% EtOAc/hexane (1.25 L) to provide (R)-benzyl 3-(tert-butoxycarbonyl(methyl)amino)piperidine-1-carboxylate (4.10 g, 79% yield) as an oil. LCMS (APCI+) m/z 349 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:22]=[CH:21][C:12]3[C:13]([C:17]([NH:19][CH3:20])=[O:18])=[C:14]([CH3:16])[O:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>CN(C=O)C>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:28][C:2]2[N:7]=[C:6]([O:8][C:9]3[CH:22]=[CH:21][C:12]4[C:13]([C:17]([NH:19][CH3:20])=[O:18])=[C:14]([CH3:16])[O:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: CNC(=O)c1c(C)oc2cc(Oc3ccnc(Cl)n3)ccc12
Reactant: COc1cccc(N)c1
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C)oc2cc(Oc3ccnc(Nc4cccc(OC)c4)n3)ccc12
Temperature: 60 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
6-(2-chloropyrimidin-4-yloxy)-N,2-dimethylbenzofuran-3-carboxamide (0.1 mmol) and 3-methoxyaniline (0.1 mmol) were dissolved in 0.5 ml DMF. To this was added p-TsOH monohydrate (0.2 mmol). The reaction mixture was stirred at 60° C. for 5 hours, and subjected to extraction with ethyl acetate. Then water was added and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated. The resulting residue was purified by column chromatography to provide the title product in a yield of 80%.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([O:10]C)[C:3]=1[C:4]#[N:5].Br[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:14]=O>CCO.C(Cl)Cl>[OH:10][C:6]1[CH:7]=[CH:8][N:9]2[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:1]=[C:2]2[C:3]=1[C:4]#[N:5]
Reactant: COc1ccnc(N)c1C#N
Reactant: O=CC(Br)c1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: N#Cc1c(O)ccn2c(-c3ccccc3)cnc12
Temperature: 160 °C
Yield: 84 %

Procedure:
A mixture of compounds D3 (2 g, 13.41 mmol) and D4 (6.69 g, 33.5 mmol) in EtOH (10 ml) was subjected to microwave heating at 160° C. for 45 min. The reaction mixture was cooled to room temperature and then diluted with DCM, causing a solid to precipitate. The solid obtained was filtered off, washed thoroughly with DCM and dried in vacuo to yield compound D5 (2.65 g, 84%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[S:30][C:31]([S:34][CH3:35])=[CH:32][CH:33]=1)[CH:7]=[CH:6]2.[O:36]1CCCC1.CO.S(O)([O-])(=O)=O.S(O)(OO)(=O)=O.[K+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[S:30][C:31]([S:34]([CH3:35])=[O:36])=[CH:32][CH:33]=1)[CH:7]=[CH:6]2
Reactant: C1CCOC1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(SC)s3)ccc2c1
Agent: O=S(=O)(O)OO
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)=O)s3)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Add 1-(2-(4-(6-methoxy-2-(5-(methylthio)thiophen-2-yl)naphthalen-1-yloxy)phenoxy)ethyl)piperidine (84 mg, 0.17 mmol), tetrahydrofuran (3.3 mL) and methanol (3.3 mL) to a round bottom flask under nitrogen. Cool the resulting solution to 0° C. and add solution of potassium peroxymonosulfate sulfate (102 mg; 0.17 mmol) in water (1.7 mL). Stir the resulting mixture at 0° C. for 30 min. Load the mixture onto an SCX acidic ion exchange column. Flush the column with 1:1 methanol/dichloromethane and elute with 1:1 2M ammonia in methanol/dichloromethane. Concentrate the ammonia containing eluent in vacuo to give the title compound (87 mg, 0.17 mmol): mass spectrum (m/z): 522 (M+1).
Reaction SMILES: [I-].CC(OC([N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)(C)C.[H-].[Na+].[I:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41](=[O:46])[C:40]2=O.CC(C)=O>CN(C=O)C>[I:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41](=[O:46])/[C:40]/2=[CH:14]\[C:10]1[NH:9][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: CC(C)(C)OC(=O)n1cccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: O=C1Nc2ccc(I)cc2/C1=C/c1ccc[nH]1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of [[1-[[(1,1-dimethylethyl)oxy]carbonyl]-1H-pyrrol-2-yl]methyl]triphenylphosphonium iodide (2.3 g, 4.0 mmol) (prepared according to the procedure of: V. H. Rawal et. al., J. Org. Chem. 1987, 52(1), 19-28) in 36 mL DMF at 0° C. under argon, was added slowly NaH (0.13 g, 5.4 mmol). The mixture was stirred at 0° C. for 45 min. The solution was then allowed to warm to room temperature and 5-iodoisatin (1.0 g, 3.66 mmol) was added. The solution was heated at reflux for 15 h, at which time acetone (1 mL) was added and the solvent mixture was evaporated. The residue was then purified via flash column chromatography (25% EtOAc/hex) to yield (Z)-1,3-dihydro-5-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 1.05 g, 83%).