Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:13])([O:6][CH2:7][C:8]1[S:12][CH:11]=[CH:10][CH:9]=1)[O:2][CH:3](Cl)[CH3:4].[C:14]([NH:17][C:18]1[C:19]([I:34])=[C:20]([N:29]([C:31](=[O:33])[CH3:32])[CH3:30])[C:21]([I:28])=[C:22]([C:25]([O-:27])=[O:26])[C:23]=1[I:24])(=[O:16])[CH3:15].[K+].[I-].[K+]>CN(C=O)C>[C:14]([NH:17][C:18]1[C:19]([I:34])=[C:20]([N:29]([C:31](=[O:33])[CH3:32])[CH3:30])[C:21]([I:28])=[C:22]([C:25]([O:27][CH:3]([O:2][C:1]([O:6][CH2:7][C:8]2[S:12][CH:11]=[CH:10][CH:9]=2)=[O:13])[CH3:4])=[O:26])[C:23]=1[I:24])(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: CC(Cl)OC(=O)OCc1cccs1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(C)OC(=O)OCc2cccs2)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 96 h

Procedure:
1-Chloroethyl thenyl carbonate (2.43 g, 11 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (6.66 g, 10 mmol) and potassium iodide (0.17 g, 1 mmol) in dry DMF. After stirring at 50° C. for 5 hours and at room temperature for 4 days the solvent was removed at reduced pressure. The residue was suspended in chloroform (100 ml) and washed three times with a saturated sodium hydrogen carbonate solution and finally twice with water. After drying with magnesium sulfate the solution was evaporated to dryness. Yield: 7.9 g. Purity by HPLC: 88%. 1H-NMR (DMSO-d6): delta=1.64 (CHCH3); 1.65 (N(CH3)COCH3); 2.05 (NCOCH3 ); 2.95 (NCH3); 5.41 (CH2); 7.00 (CHCH3); 7.05; 7.25; 7.61 (thiophene); 10.11 ppm (NH).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][C:12]([N:16]3[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]3)=[CH:13][CH:14]=2)[N:9]([CH3:23])[CH:8]=1)=[O:6].Br[CH2:25][C:26]1[C:27]([C:34]2[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:41])=[N:28][O:29][C:30]=1[CH:31]([CH3:33])[CH3:32].[NH4+].[Cl-]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][C:12]([N:16]3[CH2:21][CH2:20][CH:19]([O:22][CH2:25][C:26]4[C:27]([C:34]5[C:35]([Cl:41])=[CH:36][CH:37]=[CH:38][C:39]=5[Cl:40])=[N:28][O:29][C:30]=4[CH:31]([CH3:33])[CH3:32])[CH2:18][CH2:17]3)=[CH:13][CH:14]=2)[N:9]([CH3:23])[CH:8]=1)=[O:6]
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CBr
Reactant: COC(=O)c1cn(C)c2cc(N3CCC(O)CC3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COC(=O)c1cn(C)c2cc(N3CCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)CC3)ccc12
Reaction time: 6 h
Yield: 19.1 %

Procedure:
Sodium hydride (60%, 93 mg, 1.2 equiv, 2.3 mmole) is added at room temperature under nitrogen atmosphere to a solution of 6-(4-hydroxy-piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic acid methyl ester (557 mg, 1.00 equiv, 1.93 mmole), tetra-n-butylammonium iodide (73 mg, 0.1 equiv, 193 μmoles) and 4-bromomethyl-3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazole (674 mg, 1 equiv, 1.93 mmole) in anhydrous tetrahydrofuran (6 mL). The reaction mixture is stirred for 6 h. Aqueous saturated NH4Cl is added and the resulting aqueous solution is extracted with ethyl acetate. The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified via flash chromatography (40 g silica) eluting with a gradient of ethyl acetate:hexane (10% to 100%) to provide the title compound as a white solid (205 mg, 19%). ES/MS m/z 556.0 (M+1)
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C@@H:24]([OH:25])[CH2:23][CH2:22][C@@:21]2([CH3:26])[C@H:3]1[CH2:4][CH2:5][C:6]1[C:7]3[C@:17]([CH3:27])([CH2:18][CH2:19][C:20]=12)[C@@H:10]([C@H:11]([CH3:16])[CH2:12][CH2:13][CH2:14][OH:15])[CH2:9][CH:8]=3.C(O)C(N)(CO)CO.[Cl-]>C1C=CC=CC=1>[OH:25][C@H:24]1[CH2:23][CH2:22][C@@:21]2([CH3:26])[C@@H:3]([CH2:4][CH2:5][C:6]3[C:7]4[C@:17]([CH3:27])([CH2:18][CH2:19][C:20]=32)[C@@H:10]([C@H:11]([CH3:16])[CH2:12][CH2:13][CH:14]=[O:15])[CH2:9][CH:8]=4)[C:2]1([CH3:1])[CH3:28]
Reactant: C[C@H](CCCO)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Agent: NC(CO)(CO)CO
Agent: [Cl-]
Solvent: c1ccccc1
Product: C[C@H](CCC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.8 %

Procedure:
4,4-Dimethyl-5α-chola-8,14-dien-3β,24-diol (0.21 g) is dissolved in benzene (21 ml). Tris(triph chloride (1.04 g) is added and the mixture is stirred at room temperature for 20 hours. Purification by column chromatography gives the title compound (129 mg). 1H-NMR (CDCl3, 300 MHz): δ=9.79 (1H, s); 5.36 (1H, s); 1.05 (3H, s) 1.01 (3H, s); 0.95 (3H, d); 0.82 (3H, s); 0.80 (3H, s).
Reaction SMILES: CO[CH:3]([N:21]1C(=O)C2=CC=CC=C2C1=O)[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20].NN.[C:34](NN)(=O)C1C(=CC=CC=1)C(NN)=O.[OH-].[K+]>C(O)C.Cl>[NH2:21][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:34]
Reactant: COC(COCCOCCOCCOCCOCCO)N1C(=O)c2ccccc2C1=O
Reactant: NNC(=O)c1ccccc1C(=O)NN
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: CCO
Product: COCCOCCOCCOCCOCCOCCN
Temperature: 25 °C
Yield: 54 %

Procedure:
ω-methoxyhexaethylene glycol (5 mmol) and 1.85 g (10 mmol) of potassium phthalimidate were mixed with 20 ml of dry N,N-dimethylformamide and stirred for 3 hours at 120° C. under a nitrogen atmosphere. The resulting mixture was then diluted with 50 ml of CH2Cl2 and a white solid that precipitated was removed by filtration and wished with 50 ml of CH2Cl2. The combined organic solutions were washed with 100 ml of 0.1N NaOH and 100 ml of saturated NaCl, and dried over anhydrous Na2SO4. Removal of solvent under reduced pressure afforded 1-phthalimidohexaethylene glycol monomer ether as an oily product, which was used directly without further purification. The crude 1-phthalimidohexaethylene glycol monomethyl ether (ca. 5 mmol) was dissolved in 30 ml of ethanol. After the solution was heated to the reflux temperature, 0.32 ml (10 mmol) of hydrazine was added. The mixture was refluxed for 1.5 hours under a nitrogen atmosphere, cooled to room temperature, and then acidified by the addition of a few drops of 6N HCl to pH 4. The resulting mixture was refluxed for an additional 1.5 hours, cooled to room temperature, ant the phthalhydrazide which precipitated was removed by filtration and washed with 2×15 ml of ethanol. The combined solvent was then evaporated at 40° C. under reduced pressure, and then 40 ml of an ethanol solution of KOH (0.55 g, 10 mmol) was added to the residue. The precipitated potassium tosylate was removed by filtration and washed with ethanol (2×15 ml). Ethanol was then evaporated, and 80 ml of CHCl3 was added to the residue. The precipitated yellowish solid was removed by filtration and washed with CHCl3 (2×20 ml). The combined chloroform solution was then extracted with 0.1N HCl (150 ml) and 100 ml of water. The aqueous solution was then made basic with a 1N NaOH solution (to pH 11), and extracted with methylene chloride (3×100 ml). Removal of solvent under reduced pressure, followed by purification by silica gel column chromatography utilizing CH3OH/NH4OH (30%) (9/1, v/v) afforded a 54% yield of 1-amino-3,6,9,12,15,18-hexaoxanonadecane (i.e., ω-amino-hexaethyleneglycol monomethyl ether).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)[N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[N:35]1([C:40]2[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=2)[CH:39]=[CH:38][N:37]=[CH:36]1.[B][B][B][B][B][B][B][B][B][B].C(O)(C(F)(F)F)=O>>[CH2:31]([N:30]([CH2:33][CH3:34])[C:28](=[O:29])[C:25]1[CH:26]=[CH:27][C:22]([C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:44][C:43]3[CH:42]=[CH:41][C:40]([N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)=[CH:47][CH:46]=3)[CH:3]=2)[N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:23][CH:24]=1)[CH3:32]
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(N)c2)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NCc3ccc(-n4ccnc4)cc3)c2)N2CCNCC2)cc1
Yield: 78.7 %

Procedure:
Using the same method as for COMPOUND 17 and using INTERMEDIATE 5a (206 mg, 0.44 mmol), 4-(1H-imidazol-1-yl)benzaldehyde (83.6 mg, 0.49 mmol), and decaborane (16.4 mg, 0.13 mmol) afforded COMPOUND 53 (181 mg, 42% yield) as its TFA salt. This material was lyophilized from CH3CN/H2O to produce a colourless solid. Purity (HPLC): >99%; Optical purity (Chiral HPLC): >99%; 1H NMR (400 MHz, CD3OD) δ 1.09 (br t, J=6.7 Hz, 3H), 1.21 (br t, J=6.7 Hz, 3H), 2.63 (br s, 4H), 3.15-3.28 (m, 6H), 3.51 (q, J=6.1 Hz, 2H), 4.32 (s, 1H), 4.43 (s, 2H), 6.47-6.52 (m, 1H), 6.71-6.76 (m, 2H), 7.02 (t, J=8.0 Hz, 1H), 7.26 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.6 Hz, 2H), 7.76 (s, 1H), 8.05 (s, 1H), 9.44 (s, 1H). Found: C, 51.44; H, 4.89; N, 9.63. C32H38N6O×1.2 H2O×3.0 CF3COOH has C, 51.49; H, 4.94, N, 9.48%. [α]D17=−2.1 deg [c 0.872, MeOH].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[CH3:12][S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[C:21]2Cl)(=[O:15])=[O:14]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:21]1[C:20]2[C:25](=[C:16]([S:13]([CH3:12])(=[O:14])=[O:15])[CH:17]=[CH:18][CH:19]=2)[N:24]=[CH:23][CH:22]=1
Reactant: Cc1cc2cc(F)ccc2[nH]1
Reactant: CS(=O)(=O)c1cccc2c(Cl)ccnc12
Product: Cc1[nH]c2ccc(F)cc2c1-c1ccnc2c(S(C)(=O)=O)cccc12

Procedure:
The sub-title compound was prepared by the method of Example 40 step a, using 5-fluoro-2-methyl-1H-indole and 8-methanesulphonyl-4-chloroquinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[O:10]CC)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].Cl.[OH:19][NH2:20].O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:20][OH:19])=[O:10])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15]
Reactant: CCOC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NO
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(NO)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.6 %

Procedure:
Ethyl 4-chloro-3-(trifluoromethyl)phenylcarbamate (10 g, 0.0373 mol) and hydroxyl amine hydrochloride (13 g, 0.1868 mol) were refluxed in acetic acid for 12 hours and the organic layer was evaporated under vacuum to get oil. This oil was mixed with water (100 ml) and the obtained precipitate was stirred at room temperature for 1-2 hours. The obtained solid was filtered and washed thoroughly with water. The wet cake was vacuum dried at 50° C. to afford 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea (6.8 g) as a white crystalline solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH:19]1([N:25]2[C:29]([CH2:30][CH2:31][CH2:32]Cl)=[N:28][N:27]=[N:26]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C)C=O>[CH:19]1([N:25]2[C:29]([CH2:30][CH2:31][CH2:32][O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]4)=[N:28][N:27]=[N:26]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: ClCCCc1nnnn1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ccc2cc(OCCCc3nnnn3C3CCCCC3)ccc2[nH]1
Reaction time: 4 h
Yield: 50.4 %

Procedure:
Into 200 ml of dimethylformamide, 3.2 g of 6-hydroxycarbostyril, 3.3 g of potassium carbonate and 7.7 g of 1-cyclohexyl-5-γ-chloropropyltetrazole are added and stirred for 4 hours at 70° to 80° C. After the reaction is completed, dimethylformamide is removed by distillation under reduced pressure. The residue thus obtained is then extracted with 300 ml of chloroform and the chloroform layer is washed with a diluted NaOH aqueous solution and with water and next dried with Na2SO4. After removal of the drying agent by filtration, then the mother liquor is concentrated and the residue is recrystallized from chloroform to obtain 3.54 g of 6-[3-(1-cyclohexyltetrazol-5-yl)propoxy]carbostyril, in the form of colorless needle-like crystals. Melting point: 211° to 212° C.
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([OH:19])[CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])C.[BH4-].[Na+].CO.Cl>CCO.C(Cl)Cl>[CH2:12]([O:11][C:9](=[O:10])[NH:8][CH2:7][CH2:6][C@@H:5]([OH:19])[CH2:4][OH:3])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)[C@H](O)CCNC(=O)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: O=C(NCC[C@@H](O)CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
A solution of (R)-4-benzyloxycarbonylamino-2-hydroxy-butyric acid ethyl ester (2.17 g, 7.71 mmol) in EtOH (6 mL) was added dropwise at <15° C. to a suspension of sodium borohydride (583 mg, 15.4 mmol) in EtOH (4 mL). The reaction mixture was stirred at RT for 16 h, then cooled to 5° C. and treated with MeOH (3 mL), then after 30 min acidified to pH 1-2 with conc. aq. HCl solution. The reaction mixture was stirred for 1 h, then diluted with CH2Cl2, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; CH2Cl2/MeOH gradient) afforded the title compound (1.76 g, 96%). Light yellow solid, MS: 262.1 (M+Na)+.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C(C)=O.[C:12](=O)([O-:14])[O-:13].[K+].[K+].[Si]([O-])([O-])([O-])[O-].[Al+3].[Si]([O-])([O-])([O-])[O-].[Si]([O-])([O-])([O-])[O-].[Al+3].[Al+3].[Al+3].C(=O)=O>>[NH2:1][C:5]1[CH:6]=[C:7]([C:12]([OH:14])=[O:13])[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C=O
Agent: [Al+3]
Agent: [K+]
Product: Nc1ccc(O)c(C(=O)O)c1
Temperature: 220 °C
Yield: 90 %

Procedure:
p-Acetaminophenol 15 g, potassium carbonate 30 g, and aluminum silicate 45 g were added into a 500 ml autoclave, and CO2 was introduced to perform a carboxylation reaction under a reaction pressure of 3.0 MPa and heated to 220° C., maintained for 1 hour, then the reaction was terminated, cooled to 80° C., and 1500 ml distilled water was added to dissolve potassium 5-aminosalicylate. After decolorization, the aqueous phase was acidified with 20˜30% hydrochloric acid until pH=4, cooled and then filtered to obtain the product of 5-aminosalicylic acid, the content is 98% and the yield is 90%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([S:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH2:53]([S:52][C:49]1[CH:48]=[CH:47][C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:19][CH:18]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:51][CH:50]=1)[CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]
Reactant: CCCCCCSc1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCSc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (320 mg) was added toluene/ethanol/water (10/1/1, 12 ml) and then were added 4-(hexylthio)phenyl borate (199 mg) and potassium carbonate (187 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (36 mg), and the mixture was stirred at 100° C. for 14 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate/THF, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-(4-hexylthiophenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 79) (298 mg).
Reaction SMILES: O.[CH3:2][N:3]([CH3:13])[C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][N:5]=1.Br[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:2][N:3]([CH3:13])[C:4]1[N:5]=[CH:6][C:7]([C:15]2[CH:16]=[C:17]([NH2:18])[CH:19]=[CH:20][CH:21]=2)=[CH:8][CH:9]=1
Reactant: Nc1cccc(Br)c1
Reactant: CN(C)c1ccc(B(O)O)cn1
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: COCCOC
Solvent: O
Product: CN(C)c1ccc(-c2cccc(N)c2)cn1
Temperature: 25 °C
Yield: 54 %

Procedure:
2-(dimethylamino)-pyridine-5-boronic acid hydrate (0.145 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in DME (3 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.610 mL, 1.22 mmol) and Pd(PPh3)4 (0.02 g, 0.017 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (10-100% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.067 g in 54% yield.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:33]=[CH:34][CH:35]=1)[CH2:19][N:20]([CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>CCO>[CH:28]1([N:20]([CH2:19][C:18]2[CH:33]=[CH:34][CH:35]=[C:16]([NH:15][CH2:3][CH:2]([OH:1])[CH2:4][N:5]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:6]3)[CH:17]=2)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: c1ccc2c(c1)CCN(CC1CO1)C2
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(N)c1)C1CCCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1cccc(NCC(O)CN2CCc3ccccc3C2)c1)C1CCCC1
Temperature: 100 °C
Yield: 23.2 %

Procedure:
To a solution of 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (170 mg, 0.899 mmol) in EtOH (10 mL) was added tert-butyl 3-aminobenzyl(cyclopentyl)carbamate (313 mg, 1.08 mmol) and the solution heated at 100° C. in a sealed tube overnight. The solvent was then evaporated off and the residue purified by prep-TLC to give 100 mg compound as colorless oil (280 mg, 65%). LCMS (m/z): 480.3 (M+1)
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]([OH:22])[CH3:21])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[CH2:28].CC([O-])=O.[Na+]>CN(C=O)C.CS(C)=O>[C:24]1([CH3:23])[CH:31]=[CH:30][CH:29]=[C:26]([CH:27]=[CH:28][C:2]2[S:6][C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]4[CH:15]=[C:16]([CH:20]([OH:22])[CH3:21])[CH:17]=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=2)[CH:25]=1
Reactant: C=Cc1cccc(C)c1
Reactant: CC(O)c1cccc(Nc2nccc(-c3ccc(Br)s3)n2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Cc1cccc(C=Cc2ccc(-c3ccnc(Nc4cccc(C(C)O)c4)n3)s2)c1
Temperature: 100 °C
Yield: 4.3 %

Procedure:
1-{3-[4-(5-Bromothiophen-2-yl)pyrimidin-2-ylamino]-phenyl}-ethanol (20 mg, 0.056 mmol), 3-methylstyrene (22 uL, 0.168 mmol), FibreCat1001 (12 mg, 0.0056 mmol), and NaOAc (9.2 mg, 0.112 mmol) were combined in degassed DMF (0.5 mL) in an 8-mL glass vial. The reaction was heated at 100° C. for 18 hours. The mixture was diluted with DMSO, filtered and purified by preparative LCMS to afford 1-(3-{4-[5-(2-m-tolyl-vinyl)-thiophen-2-yl]-pyrimidin-2-ylamino}-phenyl)-ethanol (1.0 mg, 4.3%). 1H NMR (500 MHz, DMSO-d6) δ 1.35 (d, J=6 Hz, 3H), 2.27 (s, 3H), 4.68 (q, J=6 Hz, 1H), 5.12 (br s, 1H), 6.90 (d, J=7.5 Hz, 1H), 6.98 (d, J=16.5 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 7.18-7.26 (m, 3H), 7.32 (d, J=8 Hz, 1H), 7.38 (Br s, 1H), 7.41 (d, J=16 Hz, 1H), 7.50 (dd, J=1.5 Hz, J=8.5 Hz, 1H), 7.87 (d, J=4 Hz, 1H), 7.92 (br s, 1H), 8.34 (s, 1H), 8.40 (d, J=5 Hz, 1H), 9.57 (s, 1H). MS: m/z 414 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=O.B(Br)(Br)Br.[OH2:18]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:5][CH:6]=2)=[CH:4][C:3]([O:2][CH3:1])=[O:18])[CH:10]=[CH:11][CH:12]=1
Reactant: O
Reactant: COC1CCc2ccccc2C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)C=C(c1ccccc1)c1cccc(OC)c1
Reaction time: 0.5 h

Procedure:
A solution of 11.39 g (0.0451 mol) of the methoxy tetralone from step 7 in 250 mL CH2Cl2 is cooled in ice and treated dropwise with 29 mL of BBr3. The purple solution is kept at 0° for 0.5 hour, then at room temperature overnight. The solution is poured into H2O and extracted twice with Et2O. The Et2O is washed twice with 5% NaOH and the NaOH back extracted with Et2O. The NaOH extract is acidified with dil. HCl and extracted twice with Et2O. The Et2O is washed with sat. NaCl, dried over Mg SO4, and the solvent removed leaving 10.82 g of a brown foam. Chromatography on silica gel, eluting with CHCl3/MeOH (98:2) gives 2.05 g (19.1% yield) of the product as a pink solid. The structure is confirmed by NMR and mass spectroscopy.