Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)O>C1C=CC=CC=1.N1C=CC=CC=1>[CH3:5][CH:6]([Cl:3])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: CC(O)c1ccc(C2CCCCC2)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(Cl)c1ccc(C2CCCCC2)cc1

Procedure:
25 ml of thionyl chloride are added dropwise to a solution of 20.4 g of methyl-(para-cyclohexylphenyl)-carbinol in 100 ml of benzene and 3 ml of pyridine, and the mixture then refluxed for 5 hours. It is then poured on to ice, the aqueous mixture is extracted with ether, and the ethereal solution washed with sodium bicarbonate solution and water. When the solution is dried and the ether evaporated, α-methyl-para-cyclohexyl-benzyl chloride is obtained in the form of a dark viscous liquid which is processed directly.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:22](=[O:36])/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([OH:35])=O)=[CH:27][CH:26]=2)[CH:12]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:14]=1.C1C=CC2[N:45]([OH:46])N=NC=2C=1.C(Cl)CCl.NOC1CCCCO1>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([C:22](=[O:36])/[CH:23]=[CH:24]/[C:25]2[CH:26]=[CH:27][C:28](/[CH:31]=[CH:32]/[C:33]([NH:45][OH:46])=[O:35])=[CH:29][CH:30]=2)[CH:12]=[C:13]([N:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[CH:14]=1
Reactant: On1nnc2ccccc21
Reactant: CN1CCN(c2cc(Cl)cc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)c2)CC1
Agent: NOC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CN1CCN(c2cc(Cl)cc(C(=O)/C=C/c3ccc(/C=C/C(=O)NO)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
(E)-3-(4-{(E)-3-[3-Chloro-5-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid trifluoroacetate (40 mg, 0.076 mmol) was suspended in THF (5 ml). HOBT (16 mg, 0.116 mmol), EDC (22.3 mg, 0.116 mmol), TEA (0.04 ml, 0.291 mmol) and NH2OTHP (12 mg, 0.097 mmol) were added to the resulting mixture. The reaction was stirred at room temperature overnight and then partitioned between water and AcOEt. The organic phase was dried over Na2SO4, evaporated in vacuo and the crude product was purified by column chromatography (eluent: AcOEt/MeOH 9:1). The collected fractions were evaporated and the resulting product was dissolved in DCM and treated with HCl/Et2O for 1 h. The precipitate was filtered and purified by preparative LC-MS to give 20 mg of (E)-3-(4-{(E)-3-[3-Chloro-5-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-N-hydroxy-acrylamide as its trifluoroacetate salt.
Reaction SMILES: C1(C([NH:9][CH2:10][CH:11]2[CH2:15][O:14][C:13](=[O:16])[C:12]2([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)C)C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].CO>[OH:14][CH2:15][CH:11]1[CH2:10][NH:9][C:13](=[O:16])[C:12]1([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(NCC1COC(=O)C1(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1NCC(CO)C1(c1ccccc1)c1ccccc1
Temperature: 70 °C

Procedure:
To 750 ml. of methanol and 80.0 g. (0.22 mole) of 4-(1-phenylethylaminomethyl)-4,5-dihydro-3,3-diphenylfuran-2(3H)one was added 3.0 g. of palladium hydroxide catalyst and the mixture was shaken in three atmospheres of hydrogen at 70° C. for 18 hrs. Upon filtering starting material was found to be present; fresh catalyst was added to the solution which was shaken in three atmospheres of hydrogen at 70° C. for three more hours. After filtering the filtrate was concentrated in vacuo. The residue was dissolved in 100 ml. of ethyl acetate, and 100 ml. of isopropyl ether was added. A portion of the crystallized material was recrystallized from the same solvent system to give product melting at 145°-148° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=O.[O:14]1CCN(C2CCCC=2)CC1.Cl.[C:26]1([CH3:32])[CH:31]=[CH:30][CH:29]=CC=1>>[O:14]=[C:26]1[CH2:31][CH2:30][CH2:29][C:32]1=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1
Reactant: CC(C(=O)O)c1ccc(C=O)cc1
Reactant: Cc1ccccc1
Reactant: C1=C(N2CCOCC2)CCC1
Agent: Cl
Product: CC(C(=O)O)c1ccc(C=C2CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
A solution of 3.56 g (0.02 mole) of 2-(p-formylphenyl)propionic acid and 6.4 g (0.04 mole) of 1-morpholinocyclopentene in 40 ml of toluene was stirred at 60° C. for 3 hours. The mixture was cooled, and 20 ml of 6N hydrochloric acid were then added to the cooled solution, after which the mixture was stirred at room temperature for a further 1 hour. The reaction mixture was then extracted with diethyl ether; the extract was washed with water and dried; and the solvent was removed by evaporation under reduced pressure to afford a crystalline substance, which was recrystallized from a mixture of diethyl ether and hexane, to give 4.0 g (yield 82.3%) of the title compound as white crystals melting at 106°-107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1I.[C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)#[CH:18].C(N(CC)CC)C>O1CCCC1.[Cu]I.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>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:18]#[C:17][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C#CC1CCCCC1
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C#CC1CCCCC1
Reaction time: 8 h

Procedure:
tert-Butyl 4-chloro-3-iodopyridin-2-ylcarbamate (1.0 g, 2.82 mmol) in 10 mL tetrahydrofuran was treated with copper(I) iodide (0.027 g, 0.141 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.099 g, 0.141 mmol) and the mixture was purged with nitrogen for 5 minutes. Ethynylcyclohexane (0.472 mL, 3.67 mmol) and triethylamine (1.179 mL, 8.46 mmol) were added and the mixture was stirred overnight under nitrogen. The mixture was filtered through diatomaceous earth and the filtrate washed with aqueous citric acid (once), water (twice), and brine (once), dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography (20% ethyl acetate/hexane) provided the title compound. MS (DCI) m/e 335/337 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:4][C:5]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[O:14])=[CH:11][C:10]=2[N+:25]([O-:27])=[O:26])=[N:6][CH:7]=1.[N:34]([C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=1)=[C:35]=[O:36].C(N(CC)CC)C>C(Cl)Cl>[C:41]([C:40]1[CH:39]=[CH:38][C:37]([NH:34][C:35]([N:31]2[CH2:32][CH2:33][N:28]([C:3]3[C:2]([CH3:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]4[CH:24]=[CH:23][C:12]([C:13](=[O:14])[NH:15][CH:16]5[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]5)=[CH:11][C:10]=4[N+:25]([O-:27])=[O:26])[N:4]=3)[CH2:29][CH2:30]2)=[O:36])=[CH:44][CH:43]=1)#[N:42]
Reactant: Cc1cnc(Nc2ccc(C(=O)NC3CCN(C)CC3)cc2[N+](=O)[O-])nc1N1CCNCC1
Reactant: N#Cc1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(C(=O)NC3CCN(C)CC3)cc2[N+](=O)[O-])nc1N1CCN(C(=O)Nc2ccc(C#N)cc2)CC1
Temperature: 23 °C
Reaction time: 16 h
Yield: 222 %

Procedure:
To a solution of 4-((5-methyl-4-(piperazin-1-yl)pyrimidin-2-yl)amino)-N-(1-methylpiperidin-4-yl)-3-nitrobenzamide (0.073 mmol) in DCM (1.5 mL) was added 4-isocyanatobenzonitrile (23 mg, 0.16 mmol) and triethylamine (0.055 mL, 0.39 mmol) and the mixture was stirred at 23° C. for 16 h. reaction. The crude reaction mixture was filtered and washed with minimal volume of DCM and then hexanes to give the title compound (97 mg, 100%). MS (ES+) C30H34N10O4 requires: 598. found: 599 [M+H]+.
Reaction SMILES: C[O:2][CH:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[C:15](=[O:33])[NH:16][C:17](=[O:32])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][C:24]([N+:28]([O-:30])=[O:29])=[CH:25][CH:26]=3)[N:21]([CH3:31])[CH:20]=2)=[CH:6]1)[CH3:4].Cl.CCOC(C)=O>C1COCC1.[Cl-].[Na+].O>[OH:2][CH:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[C:15](=[O:33])[NH:16][C:17](=[O:32])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][C:24]([N+:28]([O-:30])=[O:29])=[CH:25][CH:26]=3)[N:21]([CH3:31])[CH:20]=2)=[CH:6]1)[CH3:4]
Reactant: COC(C)n1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccccc21
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)n1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.3 %

Procedure:
To a solution of 3-[l -(1-methoxy-ethyl)-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione (3.75 gm) (from step c) above) in 100 mL of THF was added 2 N HCl (75 mL). The solution was stirred at room temperature for 3 hours, and poured into EtOAc and brine. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined EtOAc layers were dried over magnesium sulfate, and evaporated. The residue was purified by flash chromatography using EtOAc/hexanes to give 1.1 gm (Yield 33%) of 3-[1-(1-hydroxy-ethyl)-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:14]3[C:25](=[O:29])[NH:26][C:27](=[O:28])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:30])[CH:8]=[CH:7][C:6]1=2.[C:31]1([SH:37])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C.O>O1CCOCC1>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[C:14]2[C:25](=[O:29])[NH:26][C:27](=[O:28])[C:13]=2[C:12]2[C:11]3[CH:10]=[C:9]([OH:30])[CH:8]=[CH:7][C:6]=3[N:5]([CH2:4][CH2:3][CH2:2][S:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:17]=2[CH:16]=1
Reactant: Sc1ccccc1
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1c2c2cc(O)ccc2n1CCCBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1c2c2cc(O)ccc2n1CCCSc1ccccc1

Procedure:
A solution of the bromide (58) (41 mg, 0.085 mmol) prepared as described in example 172, thiophenol (9.5 μL, 0.093 mmol) and triethylamine (0.25 mL, 3.40 mmol) in p-dioxane (1.5 mL) was refluxed for 16 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness the sulfide (131) directly (37.2 mg, 85%), which crystallised from ethyl acetate/petroleum ether as an orange powder, mp 229–231° C. 1H NMR δ [(CD3)2SO] 11.06 (br s, 1H), 9.37 (s, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.76 (s, 1H), 7.60–7.42 (m, 5H), 7.25–7.19 (m, 4H), 7.16–7.10 m, 2H), 4.57 (t, J=6.8 Hz, 2H), 2.98 (m, 2H), 2.01 (m, 2H). Found: C, 67.36; H, 4.29; N, 5.36. C29H21ClN2SO3.114H2O requires C, 67.31; H, 4.19; N, 5.41.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=1[O:31][CH3:32]>>[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=3)[CH2:7][CH2:6]2)=[O:27])=[CH:24][C:23]=1[O:31][CH3:32]
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: COc1cc(C(=O)O)ccc1N
Product: COc1cc(C(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)ccc1N

Procedure:
Prepared as described in Example 1 from (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1 g) and 4-amino-3-methoxybenzoic acid (0.052 g). Title compound obtained as white solid (0.053 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].C([Sn](CCCC)(CCCC)[C:16]([O:18]CC)=[CH2:17])CCC.O1CCO[CH2:31][CH2:30]1>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>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([O:18][CH2:16][CH3:17])[O:7][CH2:30][CH3:31])=[CH:4][C:3]=1[F:10]
Reactant: C1COCCO1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=Cc1ccc(Br)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(OCC)c1ccc(Br)c(F)c1
Temperature: 130 °C

Procedure:
To a solution of 4-bromo-3-fluorobenzaldehyde (1.00 g, 4.9 mmol) in dioxane (10.0 mL) was added tributyl(1-ethoxyvinyl)stannane (1.7 mL, 5.2 mmol) and Pd(PPh3)2Cl2 (0.069 g, 0.099 mmol). The resulting solution was purged with argon for 2 min and then heated (microwave) in a sealed tube at 130° C. for 30 min. The cooled reaction solution was filtered through a plug of silica gel (eluting with 80 mL EtOAc), and the filtrate was concentrated in vacuo. Chromatographic purification of the residue (ISCO, 40 g, 0-30% EtOAc/Hex) afforded 1-bromo-4-(diethoxymethyl)-2-fluorobenzene as a light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.98 (s, 1H), 7.81 (t, J=7.5 Hz, 1H), 7.65 (d, J=7.5 Hz, 1H), 7.57 (d, J=11.0 Hz, 1H), 4.90 (d, J=2.0 Hz, 1H), 4.58 (s, 1H), 3.94 (q, J=7.0 Hz, 2H), 1.42 (t, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:12][CH2:13]1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of (trans-4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester (7.0 g, 33 mmol) in CH2Cl2 (165 mL) was charged with pyridine (13 mL, 79 mmol) and methanesulfonylchloride (6.4 mL, 82 mmol). The reaction was stirred at RT for 14 h and concentrated in vacuo. The residue was dissolved in EtOAc and the resulting solution was washed successively with water (2×) and brine (1×) before being dried (MgSO4), filtered, and concentrated in vacuo to afford methanesulfonic acid trans-4-tert-butoxycarbonylamino-cyclohexyl ester (9.3 g, 96% yield). MS found: (M+H)+=294.2.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][NH:10][C:9]2[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:8]=2[O:7]1)=[O:5])C.[C:20]([O-])([O-])=O.[K+].[K+].IC.Cl>CN(C=O)C.O>[CH3:20][N:10]1[C:9]2[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:8]=2[O:7][CH:6]([C:4]([OH:3])=[O:5])[CH2:11]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1CNc2cc(C(F)(F)F)ccc2O1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN1CC(C(=O)O)Oc2ccc(C(F)(F)F)cc21
Temperature: 150 °C
Yield: 14.4 %

Procedure:
To a solution of 6-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid ethyl ester (650 mg, 2.4 mmol) in anhydrous DMF (7 mL) was added K2CO3 (816 mg, 5.9 mmol), followed by iodomethane (294 μL, 4.7 mmol). The reaction was heated in the microwave (300 W, 150° C.) for 1 hour. After cooling, the mixture was poured into water (50 mL), acidified with 2N HCl and extracted with EtOAc (3×50 mL). The combined organics were washed with brine (3×50 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (0 to 12% MeOH in DCM) gave the title compound (90 mg, 10%) as a solid. m/z=262.1 (M+1), r.t.=3.28 mins. 1H NMR (400 MHz; d6-DMSO) δ 6.93-6.86 (3H, m), 4.85 (1H, s), 3.45-3.36 (2H, m), 2.86 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[C:6]([OH:8])[CH:7]=1.[Cl-].[NH4+:11].[OH-].[NH4+]>O>[NH2:11][C:4]1[CH:5]=[C:6]([OH:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: [NH4+]
Reactant: Cc1cc(O)cc(O)c1
Agent: [Cl-]
Agent: [OH-]
Solvent: O
Product: Cc1cc(N)cc(O)c1
Temperature: 180 °C

Procedure:
A mixture of 5-methylbenzene-1,3-diol (6.0 g), ammonium chloride (3.0 g), water (9.0 mL), and ammonium hydroxide (6.8 mL, 33% in water) were sealed in a bomb and heated at 180° C. for 17 hours. The mixture was cooled to room temperature and the resulting precipitate collected by filtration. Crystallisation from water gave title compound, 1.7 g.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4]/[C:5](/[CH3:21])=[CH:6]/[CH2:7][C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH3:16])[C:11]([CH3:17])=[C:10]([CH3:18])[C:9]=1[O:19][CH3:20].[Na+].[I-:23].CC(C)=O>O>[I:23][CH2:2][CH2:3][CH2:4]/[C:5](/[CH3:21])=[CH:6]/[CH2:7][C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH3:16])[C:11]([CH3:17])=[C:10]([CH3:18])[C:9]=1[O:19][CH3:20]
Reactant: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCCl)c1C
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCI)c1C
Temperature: 25 °C
Yield: 99 %

Procedure:
(E)-1-(6-chloro-3-methylhex-2-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene (725.8 mg, 2.334 mmol) and NaI (3.09 g, 20.61 mmol) were dissolved into acetone (10 mL) and heated to reflux for 18 h. The reaction mixture was cooled to room temperature and the cloudy solution added to H2O (50 mL) and of a 50% EtOAc/hexanes solution (50 mL), the layers separated and the aqueous phase extracted with hexanes (3×25 mL), then MTBE (2×25 mL). The organics were combined and washed with saturated NaCl solution (2×25 mL) and dried over anhydrous Na2SO4. Concentration yielded 930.0 mg (99.0%) of 1-((E)-6-iodo-3-methylhex-2-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene as a pale yellow oil. 1H NMR (400 MHz, CDCl3) d 5.12 (t, J=6.4 Hz, 1H), 3.65 (s, 6H), 3.36 (d, J=6.0 Hz, 2H), 3.12 (t, J=7.2 Hz, 2H), 2.18 (S 9H), 2.07 (t, J=7.2 Hz, 2H), 1.91 (t, J=7.2 HZ, 2H), 1.77 (s, 3H), 13C NMR (100 MHz, CDCl3) d 153.1, 152.6, 133.0, 131.3, 128.4, 127.9, 127.6, 124.7, 60.9, 60.1, 40.1, 31.7, 26.1, 16.1, 12.8, 12.7, 12.2.
Reaction SMILES: [PH2](O)=[O:2].C([O:6][CH:7]([O:20][CH2:21][CH3:22])[C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)C>I>[CH:7]([O-:2])([O-:6])[O:20][CH2:21][CH3:22].[C:9]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:8]=1
Reactant: CCOC(OCC)c1ccccc1-c1ccccc1
Reactant: O=[PH2]O
Agent: I
Product: CCOC([O-])[O-]
Product: c1ccc(-c2ccccc2)cc1

Procedure:
Hydriodic acid (10 ml) and hypophosphorous acid (1 ml) were heated and stirred at ca. 100° while 1.024 g of 2-biphenyl-carboxaldehyde diethyl acetal (m.p. 63°, obtained from 2-biphenyl-magnesium iodide and ethyl orthoformate, biphenyl being removed from the crude product by draining in tile then steam-distillation. Anal. Calc. for C17H20O2 : C, 79.65; H, 7.86. Found: C, 79.48; H, 7.84) in 5 ml of acetic acid was added. The mixture was stirred and slowly distilled under the vapour reached 125° after 1 hr. The combined distillate and residue were diluted with water and the product isolated using ether. It was sublimed at <100° (5 × 10-4 mm) and crystallized from methanol as colourless prisms (83%, m.p. 117.5°-118°, mixed m.p. with authentic fluorene of m.p. 118°-119°:117.5°-119°). Anal. Calcd. for C13H10 : C, 93.94; H, 6.06. Found: C, 93.67; H, 6.20.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][NH:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](Cl)=[O:30]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][N:13]([C:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)=[O:30])[C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3
Reactant: O=C(Cl)c1cccs1
Reactant: Clc1cnc2nc1Nc1cccc(c1)NCc1cccc(c1)N2
Product: O=C(c1cccs1)N1Cc2cccc(c2)Nc2ncc(Cl)c(n2)Nc2cccc1c2
Yield: 34 %

Procedure:
The desired compound was prepared as a white powder according to the procedure of Example C22, step F, using 6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene and 2-thiophenecarbonyl chloride as the starting materials in 34% yield. LCMS for C22H17ClN5OS (M+H)+: m/z=434.0.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[CH2:4]1.C(N(CC)CC)C.[CH3:24][O:25][C:26]1[C:41]([O:42][CH3:43])=[CH:40][C:29]2[CH2:30][C:31](=[O:39])[N:32]([CH2:35][CH2:36][CH2:37]Cl)[CH:33]=[CH:34][C:28]=2[CH:27]=1>[OH-].[Na+].C(OCC)(=O)C>[CH3:24][O:25][C:26]1[C:41]([O:42][CH3:43])=[CH:40][C:29]2[CH2:30][C:31](=[O:39])[N:32]([CH2:35][CH2:36][CH2:37][N:2]([CH3:1])[CH:3]3[CH2:12][CH2:11][C:10]4[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=4)[CH2:4]3)[CH:33]=[CH:34][C:28]=2[CH:27]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)C=C2
Reactant: CNC1CCc2cc(OC)c(OC)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C1CCc3cc(OC)c(OC)cc3C1)C=C2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 2-methylamino-6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene (1.72 g, 0.0078 mol), triethylamine (1.09 ml, 0.0078 mol) and 1-(7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane (2.3 g, 0.0078 mol) is heated to a reaction temperature of 90° C. in steps within one hour and kept at this temperature for 2 hours. The initial suspension slowly changes into a clear solution and begins to precipitate in a jelly-like manner after about 30 minutes. The cooled reaction mixture is dissolved in 0.5M sodium hydroxide solution/ethyl acetate, the organic phase is washed with water, dried over magnesium sulphate, concentrated by evaporation in vacuo and purified over alumina (300 g), neutral, activity II, with methylene chloride and then with increasing quantities of ethanol (up to 20%). The hydrochloride is precipitated from a solution in acetone using ethereal hydrochloric acid. Yield: 1.39 g Mp: >125° C. (Decomp.).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].I[CH3:8].[Cl:9][C:10]1[C:19]([I:20])=[CH:18][C:13]2[NH:14][C:15](=[S:17])[NH:16][C:12]=2[CH:11]=1>CC(C)=O>[Cl:9][C:10]1[C:19]([I:20])=[CH:18][C:13]2[N:14]=[C:15]([S:17][CH3:8])[NH:16][C:12]=2[CH:11]=1
Reactant: S=c1[nH]c2cc(Cl)c(I)cc2[nH]1
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1nc2cc(I)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
K2CO3 (0.22 g, 1.61 mmol), followed by iodomethane (0.1 mL, 1.61 mmol), was added to a solution of 5-chloro-6-iodo-1,3-dihydro-2H-benzimidazole-2-thione 16-3 (1 g, 3.22 mmol) in acetone (20 mL) at 0° C. The reaction was stirred at rt for 1 h. Additional K2CO3 (1.61 mmol) and iodomethane (1.61 mmol) were added, and stirring continued at rt overnight. Volatiles were removed and the residue was partitioned between EtOAc and water. Concentration afforded the desired product 16-4 as a white foam, which was used in the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[S:15][C:14]2[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:13]=2[CH:12]=1)C1C=CC=CC=1.O1CCOCC1.[OH-].[Na+].O>C=C>[CH3:21][O:20][C:19]1[C:13]2[CH:12]=[C:11]([NH2:10])[S:15][C:14]=2[C:16]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)OCc3ccccc3)cc12
Agent: C=C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccccc2)c2sc(N)cc12
Yield: 60 %

Procedure:
A stirred solution of (4-methoxy-7-phenyl-benzo[b]thiophen-2-yl)-carbamic acid benzyl ester (1.7 g, 4.36 mmol) in ethylene gylcol and dioxane was heated under reflux with 2N NaOH (20 ml, 9.1 eq) for 4 h. After cooling and addition of water (20 ml) the mixture was extracted with EtOAc (3×25 ml), the combined extracts were washed with brine, dried with Na2SO4 filtered and evaporated. The crude residue was then chromatographed over silica gel eluting with dichloromethane/2N NH3 in MeOH (99:1). This afforded the title compound (668 mg, 60% yield) as a red gum. MS m/e=256.2 (M+)