Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.[I-].[Na+].[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.C(Cl)Cl>[C:18]([NH:22][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]1[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:2]=1[F:1])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)N
Reactant: Fc1ccc(Br)cc1COCCCCBr
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)NCCCCOCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (400 mg, 1.18 mmol) in tetrahydrofuran (6 ml) was treated with sodium iodide (242 mg, 1.6 mmol). The resulting mixture was stirred at ambient temperature. After 1.5 hours, the sodium bromide was removed by filtration, and the filtrate concentrated. The residue was treated with a tetrahydrofuran solution of tert-butylamine (1.24 ml, 11.8 mmol). The progress of the reaction was monitored by thin layer chromatography. The resulting mixture was stirred for about 19 hours at ambient temperature. The reaction mixture was diluted with methylene chloride, and washed with saturated sodium bicarbonate. The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by radial chromatography.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1)[NH2:2].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.S(=O)(=O)(O)O>>[C:13]1(=[N:2][NH:1][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][CH2:5][N:4]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCCCC1
Reactant: NNC1=NCCc2ccccc21
Agent: O=S(=O)(O)O
Product: c1ccc2c(c1)CCN=C2NN=C1CCCCC1

Procedure:
In a manner similar to that of Example 4, condensation of 1-hydrazino-3,4-dihydroisoquinoline (9.4 g.) and cyclohexanone (6.3 g.) and treatment of the reaction mixture with sulfuric acid gave an oil, which was crystallized, then recrystallized, from isopropyl alcohol-ether, affording 1-(2-cyclohexylidenehydrazino)-3,4-dihydroisoquinoline [(I: X=X'=CH2 (CH2)4C,] Y=Y'=Z=Z'=H) sulfate (15.3 g., m.p. 139°-141° C. with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.Cl[CH2:13][C:14]([CH2:16]Cl)=O.[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([CH:27]2[CH2:32][CH2:31][CH:30]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:29][CH2:28]2)[C:22]([C:41]#[N:42])=[C:21]([SH:43])[N:20]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([C@H:27]2[CH2:28][CH2:29][C@@H:30]([O:33][Si:34]([C:37]([CH3:39])([CH3:40])[CH3:38])([CH3:35])[CH3:36])[CH2:31][CH2:32]2)[C:22]([C:41]#[N:42])=[C:21]([S:43][CH2:16][C:14]2[N:11]=[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[S:10][CH:13]=2)[N:20]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)Nc1ccc(F)cc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(c2c(C#N)c(N)nc(S)c2C#N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](c2c(C#N)c(N)nc(SCc3csc(Nc4ccc(F)cc4)n3)c2C#N)CC1
Reaction time: 3 h

Procedure:
43 mg (0.26 mmol) of 4-fluorophenylthiourea and 31 mg (0.24 mmol) of 1,3-dichloroacetone are dissolved in 2 ml DMF and stirred at +80° C. for 3 h. After cooling to RT 93 mg (0.23 mmol) of the compound from Example 12A (cis isomer) and 78 mg (0.93 mmol) of sodium bicarbonate are added, and the reaction mixture is stirred at RT for 20 h. The mixture is then directly purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:26])=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)(=[O:14])=[O:13].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[Cl:26][C:19]1[CH:18]=[C:17]2[C:16](=[C:25]3[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]3)[NH:15][S:12](=[O:13])(=[O:14])[C:3]1[C:2]2=[CH:7][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)c3cccnc23)c(N)c1
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Yield: 11.1 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-N-(5-chloro-quinolin-8-yl)-4-methanesulfonyl-benzenesulfonamide (Intermediate 274) (205 mg, 0.5 mmol), t-butyl nitrite (0.09 ml, 0.75 mmol), AcOH (4 ml) and THF (4 ml) gave the title compound (22 mg, 16%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].C(Cl)(=O)C1C=CC=CC=1.[NH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[CH2:21][CH2:20][CH2:19][CH2:18]2.[OH-].[NH4+]>CC(C)=O.C(O)C>[CH3:26][O:25][C:24]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:16][C:15]=1[NH:14][C:2]([NH2:3])=[S:1]
Reactant: COc1cc2c(cc1N)CCCC2
Reactant: N#C[S-]
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(Cl)c1ccccc1
Solvent: CCO
Solvent: CC(C)=O
Product: COc1cc2c(cc1NC(N)=S)CCCC2
Yield: 80 %

Procedure:
1.45 g of ammonium thiocyanate are dissolved in 30 ml of acetone and after 2.2 ml of benzoyl chloride have been added, the reaction mixture is heated under reflux for 15 minutes. 2.6 g of 6-amino-7-methoxy-1,2,3,4-tetrahydronaphthalene (Compound 4-1) dissolved in 20 ml of acetone are added and then the mixture is heated under reflux for 30 minutes. It is evaporated to dryness, the residue obtained is taken up in a minimum of ethanol, 50 ml of 30% ammonium hydroxide are added and the mixture is heated under reflux for 20 hours. The thiourea obtained is cooled, filtered, washed with waer and then with an ethyl acetate/hexane 25/75 (v/v) mixture. 2.8 g of the expected product are obtained in the form of a beige powder; yield=80%.
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.C([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)#N>ClCCl>[CH3:27][O:26][C:24]([C:23]1[CH:28]=[CH:29][C:20]([C:12]2[N:11]3[C:7](=[N:8][C:9]4[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=43)[S:6][N:5]=2)=[CH:21][CH:22]=1)=[O:25]
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nsc3nc4ccccc4n23)cc1

Procedure:
A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (0.3 g, 1.2 mmole) and methyl 4-cyanobenzoate (0.41 g, 2.5 mmole) in 7 mL of dichloromethane was heated to reflux for 20 h. The precipitate was filtered and washed with dichloromethane to give 0.16 g (48%) of 3-([4-(methoxycarbonyl)]phenyl-1,2,4-thiadiazolo [4,5-a]benzimidazole as a white solid: mp 204-206° C.; 1H NMR (CDCl3)δ 8.33 (d, 2H), 7.98 (d, 2H), 7.83 (d, 1H), 7.49 (m, 2H), 7.20 (t, 1H), 4.02 (s, 3H) ppm; 13C NMR (CDCl3)δ 165.96, 165.30, 151.08, 149.10, 133.16, 132.55, 130.24(2C), 128.69(3C), 125.34, 121.58, 119.96, 112.01, 52.56 ppm; IR (KBr)ν 1729, 1508, 1448, 1275, 733 cm-1 ; HRMS calcd for C16H11N3OS, 309.0572 found 309.05719.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=[CH2:11])=[CH:5][CH:4]=1.B(Br)(Br)Br.[B]>C(Cl)Cl>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1)[CH:10]=[CH2:11]
Reactant: C=CCc1ccc(OC)cc1
Agent: BrB(Br)Br
Agent: [B]
Solvent: ClCCl
Product: C=CCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To 50.01 g (337.4 mmol) of 1-methoxy-4-(2-propenyl)benzene (Aldrich Chemical Company, Milwaukee, Wis.) dissolved in 300 mL of anhydrous methylene chloride was added dropwise 375 mL (375 mmol) of 1.0 M boron tribromide (Aldrich) in methylene chloride. The reaction was run under nitrogen at room temperature and the mixture was stirred for 1 hour. The mixture was poured over 1000 mL of crushed ice, stirred for 5 minutes, and transferred to a separatory funnel. The organic layer was drained and saved. The boron salts were transferred to a filter containing Celite™ (Aldrich Chemical Co., Milwaukee, Wis.) and the filter containing the salts was washed with portions of methylene chloride and then water. The filtrate was transferred to a separatory funnel and the organic and aqueous layers were separated. The aqueous layer was extracted with four 100mL portions of methylene chloride. The methylene chloride solutions were pooled, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under vacuum to yield 25.27 g (56%) of crude 4-(2-propenyl)phenol. The crude product was distilled twice at reduced pressure to yield 20.34 g (45%) of 4-(2-propenyl)phenol. The NMR data was consistent with that reported by Rajashekhar and coworkers (J. Biol. Chem. 1984, 259, 6925).
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15](O[Si](CC(C)C)(C)C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.[CH2:40]1COCC1.O>>[CH3:39][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:40])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:37][CH:38]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O[Si](C)(C)CC(C)C)cc2)=CCC3(C)C)cc1
Solvent: O
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1

Procedure:
A solution of 142.6 mg (0.339 mmol) of ethyl 4- [(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2- naphthalenyl)ethynyl]benzoate (Compound 1) and 35.6 mg (0.848 mmol) of LiOH--H2O in 12 ml of THF/water (4:1, v/v), was stirred overnight at room temperature. The reaction mixture was extracted with hexanes, and the hexane fraction extracted with 5% aqueous NaOH. The aqueous layers were combined and acidified with 1M HCl, and then extracted with EtOAc and Et2O. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6 -DMSO): δ 7.91 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz), 7.47 (2H, s), 7.23 (4H, q, J=8.1 Hz), 7.01 (1H, s), 6.01 (1H, t, J=4.6 Hz), 2.35 (3H, s), 2.33 (2H, d, J=4.8 Hz), 1.30 (6H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:11][C:10](=O)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1(P(=[CH:33][C:34]([O:36][CH3:37])=[O:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:37][O:36][C:34](=[O:35])[CH:33]=[C:10]1[CH2:11][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])[CH2:9]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C=C1CC(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 1450.6 %

Procedure:
To a solution of (3-oxo-cyclobutyl)-carbamic acid tert-butyl ester (5.6 g, 30 2 mmol) in anhydrous toluene (100 mL) was added methyl (triphenylphosphoranylidene)acetate (10.7 g, 45.4 mmol) and heated to reflux overnight under N2. After cooling to room temperature, the mixture was poured into water and extracted with EA. The organic phase was dried over Na2SO4, concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (eluted with PE:EA=20:1) to give the title compound (7 g, yield 96%) as a white solid.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)[CH3:2].[Li+].[C:9]([O-:14])(=[O:13])[CH2:10][CH:11]=C.[CH2:15]([C:19]1[N:20]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[Cl:43])[C:21](/[CH:24]=[C:25](\[CH2:30][C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)/C(OC)=O)=[CH:22][N:23]=1)[CH2:16][CH2:17][CH3:18].CI>O1CCCC1.[Cl-].[NH4+]>[CH2:15]([C:19]1[N:20]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[Cl:43])[C:21](/[CH:24]=[C:25](\[CH2:30][C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)/[CH:10]([CH3:11])[C:9]([O:14][CH2:1][CH3:2])=[O:13])=[CH:22][N:23]=1)[CH2:16][CH2:17][CH3:18]
Reactant: C=CCC(=O)[O-]
Reactant: CC(C)[N-]C(C)C
Reactant: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)OC)n1Cc1ccccc1Cl
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(C)C(=O)OCC)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium diisopropylamide (0.85 mmol, 1M in tetrahydrofuran) is cooled to -78° under argon and a solution of ethyl (E)-4-[2-n-butyl-1-[(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-3-(2-thienyl)methyl)-3-butenoate (0.709 mmol), prepared as in Example 13 using methyl (E) 3-[2-n-butyl-1-[(2-chlorophenyl)methyl]-1H-imidazol-5-yl]-(2-thienyl)methyl-2-propenoate (Example 1), in tetrahydrofuran (5 mL) is added. After 10 minutes methyl iodide (0.71 mmol) is added. The mixture is then stirred at room temperature overnight, diluted with 10% ammonium chloride and extracted with ethyl acetate. The dried, concentrated product is chromatographed over silica gel with 6:4 hexanes/ethyl acetate to give the title compound. (ii) (E)-1-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-3-methyl-3-(1H-tetrazol-5-yl)-2-(2-thienyl)methyl-1-propene
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:13]([OH:14])=[CH:12][C:11]2[C:10]([CH3:16])([CH3:15])[CH2:9][CH2:8][C:7]([CH3:18])([CH3:17])[C:6]=2[CH:5]=1.I[CH3:20].O>CN(C=O)C>[Br:3][C:4]1[C:13]([O:14][CH3:20])=[CH:12][C:11]2[C:10]([CH3:16])([CH3:15])[CH2:9][CH2:8][C:7]([CH3:18])([CH3:17])[C:6]=2[CH:5]=1
Reactant: CC1(C)CCC(C)(C)c2cc(Br)c(O)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Reaction time: 2 h

Procedure:
720 mg (24 mmol) of sodium hydride (80% in oil) and 20 ml of DMF were introduced into a three-necked flask, a solution of 5.7 g (20 mmol) of 2-bromo-3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene in 75 ml of DMF was added dropwise and stirring was carried out until gas evolution had ceased. 1.5 ml (24 mmol) of iodomethane was then added and stirring was carried out at room temperature for two hours. The reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was triturated in heptane and filtered. 5.5 g (93%) of 2-bromo-3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene, with a melting point of 70°-71° C., were recovered.
Reaction SMILES: [S:1](=[O:4])(=[O:3])=[O:2].N.[NH2:6][S:7]([O-:10])(=[O:9])=[O:8].[NH4+].[NH2:12][S:13]([OH:16])(=[O:15])=[O:14].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>O>[NH4+:6].[N:12]([S:7]([O-:10])(=[O:9])=[O:8])([S:13]([O-:16])(=[O:15])=[O:14])[S:1]([O-:4])(=[O:3])=[O:2]
Reactant: NS(=O)(=O)O
Reactant: O=S(=O)=O
Reactant: NS(=O)(=O)[O-]
Agent: N
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: O=S(=O)([O-])N(S(=O)(=O)[O-])S(=O)(=O)[O-]

Procedure:
U.S. Pat. No. 3,661,516 describes a process in which the reaction of sulfur trioxide and ammonia is carried out in the presence of an amount of ammonia exceeding the amount stoichiometrically necessary for the formation of ammonium amidosulfonate, and at a temperature at which a melted reaction mixture is obtained. The hot reaction mixture is to be reacted preferably with water, in which process step ammonium amidosulfonate, amidosulfonic acid and ammonium sulfate are formed from ammonium-imidodisulfonate and ammonium-nitrilo-trisulfonate. By adding strong mineral acids, the crystallization may be carried on.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](=[O:11])[CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[ClH:1].[N:12]1([CH2:2][CH2:3][C:4](=[O:11])[CH2:5][C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=C(CCCl)Cc1cccs1
Reactant: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cl
Product: O=C(CCn1ccnc1)Cc1cccs1

Procedure:
18.9 g (0.10 mol) of 4-chloro-1-(2-thienyl)butanone are run into a solution, maintained at about 90° C., of 15 g (0.22 mol) of imidazole in 35 ml of toluene, and the mixture is heated to reflux for 4 hours. The reaction medium is diluted with ethyl acetate and the mixture is washed with water and extracted with dilute hydrochloric acid solution.The aqueous phase is alkalinised with sodium hydroxide and extracted with ethyl acetate, which is dried over dry sodium sulphate. The solution is treated with a solution of hydrogen chloride in ethanol, and the insolublematter purified by a wash in acetone, to give 6 g of a water-soluble, beigepowder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:18]1[CH:19]=[CH:20][C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:22])=[CH:16][CH:17]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)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: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccccc2Cl)cc1
Yield: 83.3 %

Procedure:
2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 2-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.060 g (82%) of 2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: Br[CH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[S:4]1.C(C(C(C(O)=O)O)O)(O)=O.[CH2:28]([O:30][C:31]([C@@H:33]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]1)=[O:32])[CH3:29].C(Cl)(Cl)Cl>C1C=CC=CC=1>[CH2:28]([O:30][C:31]([C@@H:33]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:2][CH:3]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[S:4]2)[CH2:34]1)=[O:32])[CH3:29]
Reactant: BrCC1Sc2ccccc2Oc2ccccc21
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)[C@@H]1CCCN(CC2Sc3ccccc3Oc3ccccc32)C1
Yield: 53 %

Procedure:
A mixture of 11-bromomethyl-11H-dibenz[b,f][1,4]oxathiepine (6.15 g, 20 mmol, prepared similarly as described in Coll. Czech. Chem. Commun. 50, 1484, 1985), (R)-3-piperidinecarboxylic acid ethyl ester tartrate (4.7 g, 30 mmol) and chloroform (10 ml) was warmed to achieve dissolution. The solution was then allowed to stand for 1 week at room temperature, and was subsequently heated at reflux temperature for 7 h. After cooling, the mixture was diluted with benzene and washed with 5% ammonia. The organic phase was dried (potassium carbonate) and evaporated. The residue was purified by column chromatography on silica gel (55 g) using first benzene and then diethyl ether as eluents to give 4.1 g (53%) of (R)-1-(11H-dibenz[b,f][1,4]oxathiepin-11-ylmethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl.C(OCC)(=O)C>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:6]([NH2:8])=[O:5])[CH2:26][CH2:25]1.[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCNCC1
Agent: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCN(C(N)=O)CC1
Reaction time: 18 h

Procedure:
Combine 1-tert-butoxycarbonyl-4-phenyl-piperidine-4-carboxylic acid (14.5 g, 47.5 mmol) and N-methylpiperazine (12 mL, 108 mmol) in dichloromethane (450 mL), Add HOBt (8.0 g), EDC (11.2 g). After 18 hours, evaporate in vacuo to give a residue, dissolve the residue in ethyl acetate, and extract repeatedly with water. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give 1-tert-butoxycarbonyl-4-phenyl-piperidine-4-carboxylic acid 4-methylpiperazine-amide: Rf =0.33 (6% methanol/dichloromethane).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-:12].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:12][C:2]1[CH:10]=[CH:9][C:8]([C:4]([C:3]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=2[Cl:1])=[O:5])=[CH:7][CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)c(Cl)c1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: Cc1ccc(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 152.8 %

Procedure:
A stirred 80° C. solution of 2-chloro-4-methylbenzoyl chloride (6.6 g, 39 mmol) in chlorobenzene (10 ml) was treated with aluminum chloride (5.14 g, 38.5 mmol) in portions over 15 minutes. The mixture was stirred 15 hours at 80° C., cooled, quenched by addition of ice and concentrated hydrochloric acid (5 ml), and extracted three times with diethyl ether. The combined extracts were washed with water and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and evaporated under vacuum. The residue was chromatographed on a column of silica gel (250 g) eluted with 7:3 (v/v) n-hexane-dichloromethane to provide 7.9 g (76%) of 4-(4-chlorobenzoyl)-3-chlorotoluene, m.p. 58°-60.5° C.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH3:24])[CH:16]=1.C=O>C1COCC1.O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:22][CH:23]=1)[C:19](=[O:21])[O:20][CH2:1][CH2:24]2
Reactant: COc1ccc(C(=O)O)c(C)c1
Reactant: CC(C)NC(C)C
Agent: C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCOC2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (33.5 ml) in dry THF (190 ml) was added dropwise, at −78° C., n-butyllithium (1.6 M solution in hexane, 145.9 ml). Subsequently, the reaction mixture was warmed to room temperature for 5 minutes and then cooled again to −78° C., and a solution of 4-methoxy-2-methylbenzoic acid (10 g) in dry THF (210 ml) was added dropwise. After stirring at this temperature for 10 minutes, paraformaldehyde (7 g) was added. The reaction mixture was then allowed to come to room temperature and stirred at this temperature for 4 hours. The reaction mixture was admixed with water, then the THF was removed under reduced pressure and then the aqueous phase was extracted with diethyl ether. The aqueous phase was acidified with conc. HCl, and the resulting precipitate was filtered off and washed repeatedly with water. The product was thus obtained with the molecular weight of 178.06 (C10H10O3); MS (ESI): 179 (M+H+).