Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][NH:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].CCN(C(C)C)C(C)C.Br[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.CCOCC>[CH2:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1CNCCC1=O
Reactant: BrCCc1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC1CN(CCc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 3-Butyl-piperidine-4-one (250 mg) in DMF (5 ml) was added DIPEA (468 mg) and then a solution of (2-bromoethyl)-benzene (373 mg) in DMF (5 ml) over a period of 45 min. The resulting mixture was stirred at RT for 1 hour and then heated to 60° C. for 6 hours. The reaction mixture was cooled, diluted with ether and the organic solution was washed with 10% aq. Na2CO3 solution twice and brine. The organic layer was dried over MgSO4, filtered and evaporated to give a residue which was purified by flash chromatography (ethyl acetate/hexanes 1:3) to give the product as a colorless liquid (355 mg). MS (ESI): 260.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:18])[N:6]([CH2:8][CH2:9][C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[CH:4][C:5](=[O:18])[N:6]([CH2:8][CH2:9][C:10]#[C:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:7]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=c1ccc(Br)cn1CCC#Cc1ccccn1
Product: O=c1ccc(-c2ccc(F)cc2)cn1CCC#Cc1ccccn1
Yield: 35.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 83, from 5-bromo-1-(4-pyridin-2-yl-but-3-ynyl)-1H-pyridin-2-one (50 mg, 0.16 mmol) and 4-fluorophenylboronic acid (35 mg, 0.25 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 18 mg (57 μmol, 34%) of 5-(4-fluoro-phenyl)-1-(4-pyridin-2-yl-but-3-ynyl)-1H-pyridin-2-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[Li]CCCC.[B:21]([O:30][CH:31]([CH3:33])[CH3:32])([O:26][CH:27]([CH3:29])[CH3:28])OC(C)C.OC(C(O)(C)C)(C)C>O1CCCC1.CC(O)=O>[CH3:33][C:31]1([CH3:32])[C:27]([CH3:28])([CH3:29])[O:26][B:21]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=2)[O:30]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)Oc1ccc(Br)cc1C(F)(F)F
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-1-[(1-methylethyl)oxy]-2-(trifluoromethyl)benzene (D41) (5.21 g) in dry tetrahydrofuran (THF) (50 mL) was added n-BuLi (12.65 mL) dropwise at −78° C. (maintaining the temperature <−60° C.). The resulting solution was stirred at −78° C. for 30 min before triisopropyl borate (5.13 mL) was added dropwise (<−60° C.). The reaction mixture was allowed to warm to room temperature, then pinacol (0.70 g) and AcOH (2.107 mL) was added and the reaction mixture stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl, the mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine, the organic phase was dried over sodium sulphate and concentrated. The residue was purified by column chromatography to give 4,4,5,5-tetramethyl-2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,2-dioxaborolane (D42) (5.3 g) as a clear oil. δH (CDCl3, 600 MHz): 1.33 (12H, s), 1.36 (6H, d), 4.69 (1H, m), 6.97 (1H, d), 7.88 (1H, d), 7.99 (1H, s). MS (ES): C15H22BF3O3 requires 330. found 331.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1C=CC=CC=1>[Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[O:12])[CH3:11]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC(=O)Nc1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
To a solution 2.06 g (12.71 mmol) of 2,3-dichloroaniline (16-1) in 10 mL of benzene cooled in an ice bath was added drop wise a 10 mL benzene solution of 1.95 g (19.07 mmol) of acetic anhydride. The reaction mixture was then brought to reflux for 1 hour, cooled to room temperature and filtered off the desired product 16-2. MS (M+1): theoretical 203.0; measured 204.1. 1H NMR (CDCl3): 2.26 (s, 3H), 7.21 (m, 2H), 7.68 (m, 1H), 8.33 (m, 1H).
Reaction SMILES: C([NH:11][CH2:12][CH2:13][S:14]([NH2:17])(=[O:16])=[O:15])(OCC1C=CC=CC=1)=O.[C:18]([OH:25])(=[O:24])[CH2:19][CH2:20][C:21]([OH:23])=[O:22]>CO.[Pd]>[C:18]([OH:25])(=[O:24])[CH2:19][CH2:20][C:21]([OH:23])=[O:22].[NH2:11][CH2:12][CH2:13][S:14]([NH2:17])(=[O:16])=[O:15]
Reactant: NS(=O)(=O)CCNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C(O)CCC(=O)O
Solvent: CO
Product: NCCS(N)(=O)=O

Procedure:
Take a suspension of 100 g of Cbz-Taurinamide in 1000 ml methanol, and 10% Pd/C (1.0 g) and subject to hydrogenation at 45-50 psi. Upon completion of the reaction filter the catalyst and add succinic acid (1.0 eq) to the solvent and distill off the solvent under vacuum to provide the title compound in about 90% yield as a white solid.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][C@@H:6]([C:17]([O:19][CH3:20])=[O:18])[CH2:5]1)=[N+:2]=[N-:3].[ClH:21]>CO>[ClH:21].[N:1]([C@H:4]1[CH2:9][NH:8][CH2:7][C@@H:6]([C:17]([O:19][CH3:20])=[O:18])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: COC(=O)[C@H]1C[C@H](N=[N+]=[N-])CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1CNC[C@H](N=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of 1-tert-butyl 3-methyl trans-5-azidopiperidine-1,3-dicarboxylate (343.0 mg) in MeOH (1 ml) was added 10% solution of HCl in MeOH (15 ml). After stirring for 30 minutes at room temperature, the mixture was concentrated to give the crude methyl cis-5-azidopiperidine-3-carboxylate hydrochloride (120.3 mg) as a pale brown solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([CH3:33])([CH3:32])[C:30]#[N:31])[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:35].C(=O)([O-])[O-].[Na+].[Na+]>>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([CH3:33])([CH3:32])[C:30]([NH2:31])=[O:35])[CH2:25][CH2:24]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(C(C)(C)C#N)CC3)cc1OCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(C(C)(C)C(N)=O)CC3)cc1OCC2
Yield: 60 %

Procedure:
To 2-{-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionitrile (312 mg, 0.70 mmol) was added concentrated sulfuric acid (3.5 mL). The resultant mixture was stirred for 3.5 hours at RT before being poured onto ice and basified with sodium carbonate. The aqueous mixture was extracted with 10% MeOH in DCM (×5). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2, gradient 0-10% MeOH in DCM), then triturated with diethyl ether (x 3), to afford 287 (196 mg, 0.42 mmol, 60%). LCMS: RT=2.67 min, [M+H]+=464. 1H NMR δ (ppm) (DMSO-d): 8.27 (1H, d, J=8.27 Hz), 7.86 (1H, d, J=0.63 Hz), 7.85 (1H, s), 7.17 (1H, d, J=3.55 Hz), 7.03 (1H, dd, J=8.34, 1.74 Hz), 6.91-6.89 (2H, m), 5.89-5.79 (1H, m), 4.48-4.41 (4H, m), 2.80 (2H, d, J=10.82 Hz), 2.17-2.09 (2H, m), 1.77-1.60 (4H, m), 1.44 (6H, d, J=6.60 Hz), 1.05 (6H, s). 1H obscured by solvent.
Reaction SMILES: C([C:5]1[CH:9]=[C:8]([CH3:10])[S:7][C:6]=1[NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])(OC)=O.O.O.[I-].[Li+]>>[CH3:10][C:8]1[S:7][C:6]([NH:11][C:12](=[O:16])[CH:13]([CH3:14])[CH3:15])=[CH:5][CH:9]=1
Reactant: COC(=O)c1cc(C)sc1NC(=O)C(C)C
Agent: [I-]
Agent: [Li+]
Solvent: O
Product: Cc1ccc(NC(=O)C(C)C)s1
Yield: 54 %

Procedure:
The ester from Example 48 was treated with lithium iodide dihydrate as in Example 42 to give the expected decarboxylated product, N-(5-methyl-2-thienyl)-2-methylpropanamide, m.p. 96°-97° C. in 54% yield.
Reaction SMILES: B(F)(F)F.[CH3:5]COCC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:15]([OH:17])=[O:16]>CO>[CH3:5][O:16][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:12]([O:11][CH3:10])[CH:13]=1
Reactant: CCOCC
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: FB(F)F
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Yield: 101.8 %

Procedure:
Boron trifluoride diethyl etherate (2 mL, 16.3 mmol) was added to a suspension of 3-methoxy-4-nitrobenzoic acid (1.0 g, 5.07 mmol) in anhydrous methanol (15 mL) and the resulting mixture was heated at reflux for 24 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between water and dichloromethane; the aqueous layer was extracted 3 times with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified over a silica gel plug (EtOAc/hexane from 40/60 to 50/50) to give 1.09 g of 3-methoxy-4-nitro-benzoic acid methyl ester as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]Br)[CH:10]=1)[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:6]=[CH:5]2.[OH:21][CH2:22][C:23]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][O:21][CH2:22][C:23]3([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[CH:10]=1)[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: C[Si](C)(C)CCOCn1ncc2cc(Br)cc(CBr)c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc3cnn(COCC[Si](C)(C)C)c23)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A flask was charged with 5-bromo-7-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (220 mg, 0.52 mmol), tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (160 mg, 0.55 mmol), and dimethylformamide (2.5 mL). The reaction was cooled to 0° C. and treated with sodium hydride (26.4 mg, 1.1 mmol) in several portions. After stirring for 15 min, the ice bath was removed and stirring continued for 15 min. The reaction was cooled to 0° C. and quenched by the cautious addition of saturated ammonium chloride. The reaction was poured into diethyl ether, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12%→25% EtOAc/Hex) gave 233 mg (71%) as a gum. 1H-NMR (CDCl3, 500 MHz) δ 7.87 (s, 1H), 7.78 (d, J=1.5 Hz, 1H), 7.27 (d, J=1.8 Hz, 1H), 7.19 (m, 5H), 5.32 (s, 2H), 4.65 (s, 2H), 3.67 (bs, 2H), 3.41 (s, 2H), 3.36 (t, J=8.2 Hz, 2H), 3.00 (m, 2H), 2.11 (m, 2H), 1.76 (m, 2H), 1.41 (s, 9H), 0.75 (t, J=8.2 Hz, 2H), −0.10 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 155.0, 142.7, 137.1, 133.1, 131.4, 128.4, 127.8, 127.1, 126.4, 123.5, 122.8, 113.7, 79.4, 79.1, 78.8, 70.4, 66.0, 41.5, 40.2 (br), 32.1, 28.6, 17.8, −1.40.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:19])=[C:15](F)[CH:16]=3)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:25][C:26]1([NH:30]C(=O)C(F)(F)F)[CH2:29][NH:28][CH2:27]1.C(N(CC)CC)C>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:19])=[C:15]([N:28]4[CH2:29][C:26]([NH2:30])([CH3:25])[CH2:27]4)[CH:16]=3)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(F)c(F)cc2c1=O
Reactant: CC1(NC(=O)C(F)(F)F)CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1(N)CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2)C1
Yield: 51.9 %

Procedure:
A mixture of 0.8 g (2.5 mmoles) of 1-(4-fluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.3 g (6 mmoles) of 3-methyl-3-trifluoroacetamidoazetidine hydrochloride and 1 g of triethylamine is heated under reflux in 20 ml of pyridine for 3 hours. The mixture is evaporated, and extracted with methylene chloride. Filtration and evaporation yield 1.1 g of 1-(4-fluorophenyl)-6-fluoro-7-(3-trifluoroacetamido-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting at 146°-151° C., which is subsequently hydrolysed in a manner similar to that in example 41, to obtain 0.5 g (56%) of 1-(4-fluorophenyl)-6-fluoro-7-(3-amino-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting at 270°-6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][C:10]([OH:12])=[O:11])=[C:4]([F:13])[CH:3]=1.[N+]([C:17]1[CH:22]=CC=C[CH:18]=1)([O-])=O.OS(O)(=O)=O.[OH-].[Na+].Cl>OCC(CO)O.CO>[F:13][C:4]1[C:5]([CH2:9][C:10]([OH:12])=[O:11])=[C:6]([F:8])[CH:7]=[C:2]2[C:3]=1[CH:18]=[CH:17][CH:22]=[N:1]2
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Nc1cc(F)c(CC(=O)O)c(F)c1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: OCC(O)CO
Product: O=C(O)Cc1c(F)cc2ncccc2c1F
Temperature: 150 °C
Yield: 480.4 %

Procedure:
A mixture of 4-amino-2,6-difluorophenylacetic acid (3.2 g, 17.1 mmol), ferrous sulphate (1.04 g, 3.76 mmol), nitrobenzene (1.05 ml, 10.26 mmol) and conc. H2SO4 in glycerol (5.2 ml) was heated at 150° C. for 16 h. The mixture was cooled to RT, methanol (28 ml) was added followed by aq. 6N NaOH (28 ml) and heated at 110° C. for 3 h. After cooling to RT, the mixture was acidified with conc. HCl to pH 3.0. The precipitate formed was filtered, washed with water and dried under vacuum. The precipitate was refluxed with methanol, filtered under hot conditions and the filtrate was evaporated to give the title compound 11 g, 25%) as a brown solid, 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ12.72 (bs, 1H), 8.98 (d, J=3.1 Hz, 1H): 8.47 (d, J=8.4, 1H); 7.71 (d, J=9.7, 1H); 7.62 (dd, J=8.4, 4.1, 2H); 3.85 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[CH:26]=[C:25]([N:27]([CH3:51])[C:28]([N:30]([C:39]4[C:44]([Cl:45])=[C:43]([O:46][CH3:47])[CH:42]=[C:41]([O:48][CH3:49])[C:40]=4[Cl:50])[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:29])[N:24]=[CH:23][N:22]=3)=[C:16]([N+:52]([O-])=O)[CH:15]=2)=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.ClC1C=CC=CC=1.O=[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[CH:26]=[C:25]([N:27]([CH3:51])[C:28]([N:30]([C:39]4[C:40]([Cl:50])=[C:41]([O:48][CH3:49])[CH:42]=[C:43]([O:46][CH3:47])[C:44]=4[Cl:45])[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:29])[N:24]=[CH:23][N:22]=3)=[C:16]([NH2:52])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(Nc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3[N+](=O)[O-])ncn2)c1Cl
Agent: O=[Pt]=O
Solvent: CO
Solvent: Clc1ccccc1
Product: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N)ncn2)c1Cl
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To a solution of tert-butyl-4-(4-(6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)ureido)pyrimidin-4-ylamino)-3-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (380 g, 0.473 mmol) in MeOH (10 mL) was added PtO2 (38 mg, 10% wt) and one drop of chlorobenzene at room temperature, the resulting mixture was stirred under hydrogen atmosphere (1 atm) overnight. The reaction was filtered and concentrated. The residue was purified by flash chromatography on silica to obtain the title compound (130 mg, yield: 37%). MS (ESI): 776 [M+H]+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([O:37][CH3:38])=[CH:35][N:34]=[CH:33][N:32]=2)[CH2:27][CH2:26]1.C(N(CC)CC)C.C(Cl)Cl.CO>C1COCC1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[C:16]3[CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][N:28]([C:31]3[C:36]([O:37][CH3:38])=[CH:35][N:34]=[CH:33][N:32]=3)[CH2:27][CH2:26]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(N)cc23)CC1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(NS(=O)(=O)c4ccc(C)cc4)cc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
p-Toluenesulfonyl chloride (0.30 g, 1.56 mmol) was dissolved in 2 mL of THF, and the solution was cooled to 0° C. A mixture of 1-[3-[5-amino-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (0.5 g, 1.42 mmol), and triethylamine (0.16 g, 1.56 mmol) in 3 mL of THF was added to the p-toluenesulfonyl chloride solution. The solution was stirred at 0° C. for 30 min, warmed to 23° C. (1 h), and concentrated in vacuo. Silica gel column chromatography (95:5:0.5 CH2Cl2 -MeOH-30% NH4OH) of the concentrate gave 1-[3-[5-[[(4-methylphenyl)sulfonyl]amino]-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (0.42 g, 0.8 mmol, 57%). The free base (0.42 g, 0.80 mmol) was dissolved in a minimum volume of acetonitrile. A concentrated solution of oxalic acid (0.072 g, 0.8 mmol) in CH3CN was added with stirring. The precipitate was separated by filtration, washed sparingly with CH3CN and dried at 70° C. in vacuo overnight to give the title compound (0.40 g, 0.66 mmol, 82%): mp 125°-127° C. Anal. Calcd for C27H32N6O3S1.1.0 C2H2O4 : C, 55.40; H, 5.77; N, 13.36. Found: C, 55.29; H, 5.41; N, 13.15.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:19][C:20]1[S:21][C:22](Br)=[N:23][N:24]=1>C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C(O)C.O.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.C(Cl)Cl>[Br:19][C:20]1[S:21][C:22]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=2)=[N:23][N:24]=1
Reactant: Brc1nnc(Br)s1
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2nnc(Br)s2)cc1
Yield: 64.3 %

Procedure:
4-Octyloxyphenylboronic acid (5.9 g, 23.6 mmol) and 2,5-dibromo-1,3,4-thiadiazole (5.8 g, 23.6 mmol) are refluxed for 14 hours in a mixture of sodium carbonate (19.56 g), toluene (70 ml), ethanol (35 ml) and water (35 ml) and tetrakis(triphenylphosphine)palladium(0) (10 mol %) as catalyst. Aqueous work-up and column chromatography (SiO2, CH2Cl2) give 5.6 g (65% of theory) of 2-bromo-5-(4-octyloxyphenyl)-1,3,4-thiadiazole.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[CH:13]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=2)[C:28]([CH2:36][CH2:37][S:38]([C:41]2[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[CH:43][CH:42]=2)(=[O:40])=[O:39])=[C:27]1[CH2:54][CH2:55][OH:56])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(Cl)Cl>[CH:13]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=2)[C:28]([CH2:36][CH2:37][S:38]([C:41]2[CH:42]=[CH:43][C:44]([CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[CH:45][CH:46]=2)(=[O:39])=[O:40])=[C:27]1[CH2:54][CH2:55][O:56][S:2]([CH3:1])(=[O:4])=[O:3])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)CCc1ccc(S(=O)(=O)CCc2c(CCO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1ccc(S(=O)(=O)CCc2c(CCOS(C)(=O)=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
CH3SO2Cl (2 eq) and Et3N (2.5 eq) were added to a solution of ethyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (1 eq) in CH2Cl2 (0.02M) at 0° C. under N2. After 1 hour the reaction was warmed to room temperature. After an additional hour water was added and extracted with CH2Cl2 and washed with brine and dried over sodium sulfate. Removed solvent to obtain ethyl 3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propanoate (white solid) in 98% yield.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([C:14]([O:16]C)=[O:15])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[OH-].[K+].[CH3:20]O>O>[CH3:20][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[C:4]([C:14]([OH:16])=[O:15])=[CH:3][CH:2]=[CH:7][CH:6]=2)=[CH:13][CH:12]=1
Reactant: CO
Reactant: COC(=O)c1cc(C)ccc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 5 h

Procedure:
Methyl 4-methylbiphenyl-2-carboxylate (10.0 g, 44.2 mmol, 1 eq), 0.5 N KOH in methanol (265.5 ml, 133 mmol, 3 eq), and water (50 mL) were mixed and refluxed under N2. After 5 hours, the solvent was removed in ml and water (200 mL) and ethyl acetate (200 mL) added. The aqueous layer was acidified with concentrated hydrochloric acid to a pH of 3 and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×200 mL), the organic layers collected, dried (MgSO4) and the solvent removed in y3=to yield 8.71 g of a white solid; m.p. 140.0°-145.0° NMR (206 MHz, DMSO-d6 δ 7.72 (d, 1H, J=7 Hz); 7.56 (t, 1H, J=7 Hz); 7.45 (d, 1H, J=7 Hz); 7.40 (t, 1H, J=7 Hz); 7.25 (9, 411); 2.36 (s, 3H). Anal. Calcd. for C14H12O2; C, 79.23; H, 5.70. Found: C, 79.22; H, 5.47.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.Cl.Cl.[OH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH:19]1[N:24]1[CH2:29][CH2:28][C:27]2([C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH2:31][CH2:30]2)[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].[I:45][C:46]1[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=1[CH2:48]Cl>ClCCl.O.CN(C=O)C>[I:45][C:46]1[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=1[CH2:48][N:21]1[CH2:22][CH2:23][CH:18]([OH:17])[CH:19]([N:24]2[CH2:29][CH2:28][C:27]3([C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][CH2:31][CH2:30]3)[CH2:26][CH2:25]2)[CH2:20]1
Reactant: ClCc1ccccc1I
Reactant: OC1CCNCC1N1CCC2(CCCc3ccccc32)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: OC1CCN(Cc2ccccc2I)CC1N1CCC2(CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the dihydrochloride of 21c (250 mg, 0.67 mmol), DMF (10 mL), potassium carbonate (463 mg, 3.35 mmol) and 2-iodobenzyl chloride (1.00 mmol), 254 mg) was stirred at room temperature for 18 h. Water (25 mL) and dichloromethane (2×25 mL) were added and the organic layer was extracted, washed with brine (25 mL), dried (Na2SO4) and concentrated. The crude product was purified by chromatography (silica gel, hexanes/ethyl acetate, 50/50) to afford 13c as a yellow oil. The latter was converted to the corresponding hydrochloride in satd HCl/ether and recrystallized twice from 50% i-PrOH-hexanes to yield 0.20g (33%) of 13c; mp 258.8° C. 1H NMR (CDCl3) δ1.50-2.21 (2 m, 8, 2N--C H2 --C H2), 2.45-2.57 (m, 2H, Ar--C H2 --CH2, J=10.2 Hz), 2.60-2.76 (m, 2, C H2 --CHOH), 2.84 (m, 4, Ar--CH2 --C H2 --C H2), 2.88-3.00 (t, 2, C H2 --CH2 --CHOH, J=11.2 Hz), 3.09-3.13 (d, 2, N--C H2 --CHN, J=8.7 Hz), 3.50-3.64 (m, 3, Ar--CH2 --N+CH--N), 3.85 (s, 1, C H--OH), 4.67 (s, 1, OH), 6.96-7.49 (m, 8H, arom.), 7.83-7.87 (d, 1H, arom., J=6.8 Hz).