Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4](O)=O)[CH2:3][CH2:2]1.[CH3:7][C:8]1([CH3:16])[O:15][C:13](=[O:14])[CH2:12][C:10](=[O:11])[O:9]1.CCN=C=NCCCN(C)C.Cl.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[CH:1]1([CH2:4][CH:12]2[C:13](=[O:14])[O:15][C:8]([CH3:16])([CH3:7])[O:9][C:10]2=[O:11])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC1(C)OC(=O)C(CC2CC2)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
To a solution of cyclopropanecarboxylic acid (17.2 g) in methylene chloride (800 mL) were added Meldrum's acid (28.8 g), WSCI.HCl (42.2 g) and 4-dimethylaminopyridine (39.1 g), and the mixture was stirred at room temperature for 18 hr. Water and then hydrochloric acid were added to acidify the reaction mixture, and the aqueous layer was removed by partitioning. Under ice-cooling, acetic acid (114 mL) and then sodium borohydride (18.9 g) were added slowly to the organic layer, and the mixture was stirred at room temperature for 3 days. Water and then hydrochloric acid were added to the reaction mixture, and the aqueous layer was removed by partitioning. The organic layer was concentrated to give a yellow powder. This was washed with ether/hexane to give the title compound (25.8 g) as a yellow powder.
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:28]4[C:24](=[N:25][NH:26][N:27]=4)[C:23]([C:29]4[CH:34]=[CH:33][C:32]([N:35]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:31][CH:30]=4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:49]1[CH:50]=[CH:51][C:52]2[C:53](=[O:69])[N:54]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[C:55](=[O:62])[C:56]3[C:61]=2[C:60]=1[CH:59]=[CH:58][CH:57]=3.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.[Cu]I>[C:8]1([N:7]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:28]4[C:24](=[N:25][N:26]([C:59]5[CH:58]=[CH:57][C:56]6[C:55](=[O:62])[N:54]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[C:53](=[O:69])[C:52]7[C:61]=6[C:60]=5[CH:49]=[CH:50][CH:51]=7)[N:27]=4)[C:23]([C:29]4[CH:34]=[CH:33][C:32]([N:35]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)=[CH:31][CH:30]=4)=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)c4n[nH]nc34)cc2)cc1
Reactant: CCCCCCN1C(=O)c2cccc3c(Br)ccc(c23)C1=O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCN1C(=O)c2cccc3c(-n4nc5c(-c6ccc(N(c7ccccc7)c7ccccc7)cc6)ccc(-c6ccc(N(c7ccccc7)c7ccccc7)cc6)c5n4)ccc(c23)C1=O
Temperature: 160 °C

Procedure:
A mixture of Intermediate D (1.00 g, 1.65 mmol), 6-bromo-2-hexyl-1H-benzo[de]isoquinoline-1,3(2H)-dione (720 mg, 2.0 mmol), potassium carbonate (276 mg, 2.0 mmol), CuI (382 mg, 2.0 mmol), and dimethylformamide (12 mL) was stirred under argon and heated at 160° C. for 3 days. After cooling, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (3×50 mL), dried over magnesium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane/dichloromethane 1:1) and washing with ethanol to give 6-(4,7-bis(4-(N,N-diphenylamino)phenyl)-2H-benzo[d][1,2,3]triazol-2-yl)-2-hexyl-1H-benzo[de]isoquinoline-1,3(2H)-dione (Example 18), brown-violet crystals, 445 mg (30%). 1H NMR (400 MHz, CDCl3): δ 9.08 (dd, J=8.4 and 1.1 Hz, 1H, naphthalene), 8.74 (d, J=7.6 Hz, 1H, naphthalene), 7.69 (dd, J=7.3 and 1.1 Hz, 1H, naphthalene), 8.43 (d, J=8.1 Hz, 1H, naphthalene), 8.07 (d, J=8.8 Hz, 4H, p-phenylene), 7.85 (dd, J=8.4 and 7.3 Hz, 1H, naphthalene), 7.74 (s, 2H, benzotriazole), 7.28 (m, 8H, Ph), 7.21 (d, J=8.4 Hz, 4H, p-phenylene), 7.18 (m, 8H, Ph), 7.05 (tt, J=7.3 and 1.1 Hz, 4H, Ph). UV-vis spectrum (dichloromethane): λmax=381 nm. Fluorimetry (dichloromethane): λmax=481 nm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([C:17]([O:30][CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([O:15]C)=[O:14])[N:4]=1.[OH-].[K+]>O1CCOCC1.O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH:12]([C:17]([O:30][CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]([OH:15])=[O:14])[N:6]=1
Reactant: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(OC)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(OC)nc(OC(C(=O)O)C(OC)(c2ccccc2)c2ccccc2)n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2.12 g (5 mmol) of methyl 2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate were dissolved in 50 ml of dioxane, 10 ml of 1N KOH solution were added, and the mixture was stirred at 100° C. for 3 h. The solution was diluted with 300 ml of water and extracted with ethyl acetate to remove unreacted ester. The aqueous phase was then adjusted to pH 1-2 with dilute hydrochloric acid and extracted with ethyl acetate. After drying over magnesium sulfate and removal of the solvent by distillation, the residue was mixed with an ether/hexane mixture, and the precipitate which formed was filtered off with suction. After drying, 1.85 g (90%) of a white powder remained. Melting point 167° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[C:18](=[O:19])[CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[NH:14][C:13]2=[O:24])[CH2:7][CH2:6]1)=[O:4].[C:25]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH2:11][N:12]2[C:18](=[O:19])[CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[N:14]([CH3:25])[C:13]2=[O:24])[CH2:9][CH2:10]1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@H]1CC[C@H](CN2C(=O)Cc3ccccc3NC2=O)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](CN2C(=O)Cc3ccccc3N(C)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of trans-4-(2,4-Dioxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-ylmethyl)-cyclohexanecarboxylic acid methyl ester (1 mmol, 0.35 g) in DMF dry (6 mL) under argon was sequentially added K2CO3 (1.6 mmol, 0.22 g) and MeI (2.2 mmol, 140 μL). The mixture was stirred at room temperature overnight. Then H2O (10 mL) was added and the solution was loaded on a C18 cartridge, wash with water (3×5 mL) and then the desired product was eluted with MeOH. The solvent was removed under reduced pressure to give the pure titled compound (0.29 g, yield 80%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[S:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1>C1(C)C(C)=CC=CC=1>[S:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[NH:23][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4]
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1nc2ccccc2s1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2nc3ccccc3s2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 70 %

Procedure:
N-(2-Benzothiazolyl)-4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 22 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 2-amino-benzothiazole. Yield: 70% of theory, m.p. 262° C (decomp.; from xylene).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[Cl:11][C:10]1[C:2]([NH:1][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:3][C:4]([O:12][CH3:13])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C1CCCCC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(NC2CCCCC2)c(Cl)cc1C(=O)O
Reaction time: 1 h
Yield: 12.8 %

Procedure:
In a stream of argon, 3.08 g of 4-amino-5-chloro-2-methoxybenzoic acid and 1.00 g of cyclohexanone were added to 30 ml of acetic acid at room temperature, 4.30 g of sodium triacetoxyborohydride was added in small portions to the above solution, and then the resulting mixture was stirred for 1 hour. After completion of the reaction, the solvent was evaporated and the resulting residue was mixed with water, extracted with chloroform and then washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1-50:1) to give 0.37 g of 5-chloro-4-cyclohexylamino-2-methoxybenzoic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:14])[N:3]=1.[CH3:15][NH:16][NH2:17].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:15][N:16]([C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:14])[N:3]=1)[NH2:17]
Reactant: CNN
Reactant: Cc1nc(Cl)cc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1nc(-c2ccccc2)cc(N(C)N)n1

Procedure:
N-methyl-N-(2-methyl-6-phenyl-pyrimidin-4-yl)-hydrazine was prepared from 4-chloro-2-methyl-6-phenylpyrimidine (500 mg, 2.4 mmol), methylhydrazine (0.52 mL, 9.8 mmol) and potassium carbonate (506 mg, 3.7 mmol) in 5 mL of 1,4 dioxane by a procedure similar to example 3, step 1 yielding 392 mg (75%) of a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@@H:12]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17].C([C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=1)=C>CC1C=C(C)C=C(C)C=1N1CCN(C2C(C)=CC(C)=CC=2C)C1=[Ru-4](Cl)(Cl)=CC1C=C(S(N(C)C)(=O)=O)C=CC=1OC(C)C.ClCCl>[F:38][C:37]([F:39])([F:40])[C:35]1[CH:36]=[C:31](/[CH:17]=[CH:16]/[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=2[Br:1])[CH:32]=[C:33]([C:41]([F:42])([F:43])[F:44])[CH:34]=1
Reactant: C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=CCCC[C@H](NC(=O)OCc1ccccc1)c1cc(C(F)(F)F)ccc1Br
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru-4](Cl)(Cl)=Cc2cc(S(=O)(=O)N(C)C)ccc2OC(C)C)c(C)c1
Solvent: ClCCl
Product: O=C(N[C@H](CCC/C=C/c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(F)(F)F)ccc1Br)OCc1ccccc1
Temperature: 60 °C
Yield: 90.9 %

Procedure:
To a 100 mL RBF equipped with a reflux condenser was added benzyl {(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]hex-5-en-1-yl}carbamate (1.5 g, 3.29 mmol), 1-ethenyl-3,5-bis(trifluoromethyl)benzene (1.58 g, 6.57 mmol) and dichloromethane (10 mL). The system was flushed with nitrogen and 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene[2-(i-propoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]methyleneruthenium(II) dichloride (41 mg, 0.57 mmol) was added before heating at 60° C. for 20 min. The reaction was cooled to room temperature and was directly purified by column chromatography to yield benzyl {(1R,5E)-6-[3,5-bis(trifluoromethyl)phenyl]-1-[2-bromo-5-(trifluoromethyl)phenyl]hex-5-en-1-yl}carbamate (2.0 g, 2.99 mmol). 1H NMR (500 MHz, CDCl3) δ7.81 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 5.82 (m, 1H), 5.05 (m, 2H), 4.41 (m, 1H), 3.82 (s, 1H), 2.13 (m, 2H), 1.76 (m, 1H), 1.42 (m, 1H).
Reaction SMILES: Cl[C:2]1(F)[C:11]([F:12])=[C:10]2[N:5]([C:6](=[O:20])[CH:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=[C:9]2[CH2:13][CH3:14])[C:4]([F:21])=[C:3]1[F:22].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[CH2:13]([C:9]1[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6](=[O:20])[N:5]2[C:10]=1[C:11]([F:12])=[C:2]([N:28]1[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]1)[C:3]([F:22])=[C:4]2[F:21])[CH3:14]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)C1C=C(CC)C2=C(F)C(F)(Cl)C(F)=C(F)N2C1=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(CC)c2c(F)c(N3CCN(C)CC3)c(F)c(F)n2c1=O
Temperature: 85 °C

Procedure:
Ethyl 8-chloro-1-ethyl-6,7,8,9-tetrafluoro-4H-quinolizin-4-one-3-carboxylate (317 mg, 1.0 mmol), from Step 4, is dissolved in 5 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution is added 2 mL (2.0 mmol) of N-methylpiperazine and the stirred reaction mixture is heated at 85° C. for 2.5 hours. The reaction mixture is allowed to cool to ambient temperature and then concentrated in vacuo in order to remove all of the pyridine. The residue is dissolved in 50 mL of methylene chloride and the methylene chloride solution is washed with 50 mL of 5% aqueous sodium bicarbonate solution. The aqueous layer is extracted with 3 X 50 mL of methylene chloride and the combined methylene chloride solutions are dried over anhydrous sodium sulfate, filtered and concentrated and dried in vacuo to afford the title compound.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=4[F:40])[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:40][C:31]1[CH:32]=[C:33]([C:36]([F:39])([F:38])[F:37])[CH:34]=[CH:35][C:30]=1[C:22]1[CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[N:25]=[C:20]([C:16]2[CH:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=3)[CH:19]=[CH:18][CH:17]=2)[N:21]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4F)cc(C(F)(F)F)n3)c2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4F)cc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 59 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[6-(2-fluoro-4-trifluoromethylphenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.43 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as an off-white solid (0.23 g, 42%). MS (ISP) 548.1 [(M+H)+]; mp 192° C.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:6]([O:8][CH3:9])=[O:7])(=O)[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.FC(F)(F)C(O)=O>C(#N)CCC>[CH3:16][O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:1]([CH3:2])=[N:4][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: Nc1ccccc1
Reactant: COCCCCC(=O)C(NC(C)=O)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: CCCC#N
Product: COCCCCc1c(C(=O)OC)nc(C)n1-c1ccccc1
Temperature: 25 °C

Procedure:
Methyl 2-(acetylamino)-7-methoxy-3-oxoheptanoate (5.45 g), 5 aniline (3.01 ml) and trifluoroacetic acid (2.48 ml) were dissolved in butyronitrile (30 ml), and the reaction mixture was heated under reflux for 2 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. 3.6M Aqueous potassium carbonate solution was added to the obtained residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (3.88 g).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si](C(C)(C)C)(C)C)[CH:46]([O:58][CH3:59])[CH2:45]2)[CH:7]([CH3:61])[CH:6]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[CH2:5][C:4]1=[O:70])[CH3:2].F>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:58][CH3:59])[CH2:45]2)[CH:7]([CH3:61])[CH:6]([O:62][Si:63]([C:66]([CH3:67])([CH3:68])[CH3:69])([CH3:65])[CH3:64])[CH2:5][C:4]1=[O:70])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-methoxycyclohexyl)- 1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (2.91 g) in acetonitrile (15 ml) was added a solution of 2% hydrogen fluoride in aqueous acetonitrile (2 ml), and the mixture stirred at room temperature. After 4 hours, the solution was diluted with ethyl acetate, extracted with saturated sodium bicarbonate solution and the organic phase dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compound (1.51 g). (1H NMR was consistent with the desired structure).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([O-:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Na+].Br[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]2>CS(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:23]2[N:31]=[CH:30][N:29]=[C:28]4[C:24]=2[N:25]=[CH:26][NH:27]4)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: Brc1ncnc2nc[nH]c12
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1ncnc2[nH]cnc12
Temperature: 80 °C
Reaction time: 22 h
Yield: 25 %

Procedure:
A mixture of sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate [prepared according to the method of Example 10(a) Steps 1-2] (104 mg, 0.34 mmol) and 6-bromopurine (70 mg, 0.35 mmol) in dimethylsulfoxide (4 mL) was stirred at 80° C. (oil bath temperature) under nitrogen for 22 hours. The cooled reaction mixture was diluted with water (20 mL), the preciptate formed collected under suction, washed with water and dried in vacuo. Purification by flash chromatography, eluting with 5% methanol in dichloromethane, gave the title compound as a white solid (33 mg, 25%). 1H NMR (500 MHz, DMSO-d6) δ 14.06 (1H, br s), 9.04 (1H, s), 8.92 (1H, s), 8.86 (1H, s), 8.38 (1H, s), 8.35 (1H, d, J 8.7 Hz), 8.23 (1H, d, J 8.7 Hz), 8.05 (2H, m), 7.92 (2H, m), 7.38 (2H, m); m/z (ES+) 405 [MH+].
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:13][C:14]1[S:18][C:17]([Sn](CCCC)(CCCC)CCCC)=[N:16][CH:15]=1.O.CCOC(C)=O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][C:14]1[S:18][C:17]([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N:16][CH:15]=1
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncc(C)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cccc(-c2ncc(C)s2)c1
Temperature: 75 °C

Procedure:
A mixture of commercially available ethyl 3-iodobenzoate (485 mg; 1.75 mmol), 5-methyl-2-(tributylstannyl)thiazole (685 mg; 1.76 mmol), and PdCl2(PPh3)2 (123 mg; 0.17 mmol) in anh. THF (10 ml) was heated to 75° C., under nitrogen, for 18 h. In order to complete this reaction, the resulting reaction mixture was then heated to 85° C. for 8 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=1/1) afforded ethyl 3-(5-methylthiazol-2-yl)benzoate as an orange oil. LC-MS (conditions A): tR=0.88 min.; [M+H]+: 247.98 g/mol.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2([C:30](O)=[O:31])[CH2:29][CH2:28]2)=[O:26])=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[F:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]2([C:30]([NH:14][C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:16][CH:15]=3)=[O:31])[CH2:29][CH2:28]2)=[O:26])=[CH:22][CH:23]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(OCc3ccccc3)cc2)CC1
Reaction time: 3 h
Yield: 93.7 %

Procedure:
To a 0° C. suspension of 4-benzyloxyaniline hydrochloride (47.0 g, 200 mmol) and 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (49.1 g, 220 mmol) in CH2Cl2 (400 mL) was added EDCI (38.2 g, 200 mmol). Stirring was continued at rt for 2-4 h until the reaction was complete. CH2Cl2 was removed under reduced pressure. H2O (300 mL) and MeOH (200 mL) were added, and the resulting mixture was stirred at rt for 30 min. After filtration and wash with H2O, the solid was transferred to another flask containing 300 mL of sat. aqueous NaHCO3 solution. The mixture was stirred for another 30 min. The solid was filtered, washed with water, and dried over night on a lyophilizer, affording cyclopropane-1,1-dicarboxylic acid (4-benzyloxy-phenyl)-amide(4-fluoro-phenyl)-amide (75.8 g, 95% yield) as an off-white solid.
Reaction SMILES: C([NH:8][C@@H:9]([C:18]([OH:20])=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(OC(C)(C)C)=O.[CH2:21]1[C@H:30]2[C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:24][CH2:23][NH:22]1.[NH2:31][C:32]1[C:37]([Cl:38])=[CH:36][C:35]([S:39](Cl)(=[O:41])=[O:40])=[CH:34][C:33]=1[Cl:43]>>[NH2:31][C:32]1[C:37]([Cl:38])=[CH:36][C:35]([S:39]([NH:8][C@@H:9]([C:18]([N:22]2[CH2:23][CH2:24][C@H:25]3[C@@H:30]([CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21]2)=[O:20])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:41])=[O:40])=[CH:34][C:33]=1[Cl:43]
Reactant: C1CC[C@H]2CNCC[C@@H]2C1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Reactant: Nc1c(Cl)cc(S(=O)(=O)Cl)cc1Cl
Product: Nc1c(Cl)cc(S(=O)(=O)N[C@H](CCc2ccccc2)C(=O)N2CC[C@@H]3CCCC[C@H]3C2)cc1Cl

Procedure:
4-amino-3,5-dichloro-N-{(1R)-1-[(trans)-octahydroisoquinolin-2(1H) -ylcarbonyl]-3-phenylpropyl}benzenesulfonamide is prepared from Boc-(D)-homo -phenylalanine, (±)-trans-decahydroisoquinoline, and 4-amino-3,5dichlorobenzene -sulfonyl chloride in the same manner that Example 1 is synthesized. ESI MS: Calc: 523.2; Found: 524.3 (M+H)+.