Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:40][CH3:41])[C:23]([Cl:42])=[CH:22][N:21]=1>>[Cl:42][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:40][CH3:41])=[N:25][C:20]([NH:1][C:2]2[C:16]([O:17][CH3:18])=[CH:15][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:21][CH:22]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(N)=O)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCN(C)CC4)cc3OC)n1)CCN(CC(N)=O)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-acetamide and (2,5-Dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as a pale yellow solid (0.010 g, 10%). MP: 219-221° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.16 (d, 1H, J=8.3 Hz), 8.13 (s, 1H), 8.01 (s, 1H), 7.47-7.43 (m, 2H), 7.26-7.20 (m, 1H), 6.63 (s, 1H), 6.58-6.55 (m, 1H), 6.53-6.49 (m, 1H), 5.55-5.49 (m, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.32-3.27 (m, 1H), 3.22-3.17 (m, 4H), 3.11 (s, 2H), 2.96-2.90 (m, 1H), 2.89-2.85 (m, 2H), 2.81-2.87 (m, 2H), 2.74-2.67 (m, 4H), 2.64-2.58 (m, 4H), 2.38 (s, 3H). MS: 581.26 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][S:9]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10].Cl[C:23]1[N:32]=[C:31]([NH2:33])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>C(O)CC(C)C>[NH2:33][C:31]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][S:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:32]=1
Reactant: NCCCCCCNS(=O)(=O)c1cccc2ccccc12
Reactant: Nc1nc(Cl)nc2ccccc12
Solvent: CC(C)CCO
Product: Nc1nc(NCCCCCCNS(=O)(=O)c2cccc3ccccc23)nc2ccccc12

Procedure:
A solution of naphthalene-1-sulfonic acid (6-amino-hexyl)-amide (0.450 g) and 2-chloro-quinazolin-4-ylamine (see: U.S. Pat. No. 3,956,495) (0.264 g) in 20 ml of isopentylalcohol is heated up to 120° C. for 15 h. Concentration of the reaction mixture followed by chromatography on silica gel (B1) yields naphthalene-1-sulfonic acid [6-(4-amino-quinazolin-2-ylamino)-hexyl]-amide as a white powder, melting at 98-101 “C. Rf(B1) 0.28, FAB-MS: (M+H)+=450. Ananlytical C26H29N5O2S+HCl+H2O+0.6 1,4 dioxane. m.p. 98-101° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:30])[CH2:14][O:15][C:16]1[CH:17]=[C:18]([C:26]([O:28][CH3:29])=[O:27])[C:19](=[CH:24][CH:25]=1)[C:20]([O:22][CH3:23])=[O:21].C1C=CC=CC=1.[BH4-].[Na+]>CO>[CH3:29][O:28][C:26]([C:18]1[CH:17]=[C:16]([CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])[O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4])[CH3:30])=[O:27]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(OCC(C)=O)cc1C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1C(=O)OC

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 3.73 g of dimethyl 4-(2-oxopropoxy)phthalate (prepared as described in Preparation 54), 70 ml of benzene, 60 ml of absolute methanol and 1.32 g of sodium borohydride, the title compound was obtained having an Rf=0.29 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:5])[CH3:4].[Br:6][CH2:7][C:8](Br)=[O:9]>CCOCC.O>[Br:6][CH2:7][C:8]([N:2]([CH3:1])[CH:3]([CH3:5])[CH3:4])=[O:9]
Reactant: CNC(C)C
Reactant: O=C(Br)CBr
Solvent: CCOCC
Solvent: O
Product: CC(C)N(C)C(=O)CBr
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of 26 ml of methyl isopropylamine in 100 ml of ether was added to a solution of 10 ml of bromo acetyl bromide in 150 ml of ether cooled to −20° C. and the mixture was allowed to return to 20° C. The mixture was stirred for 30 minutes at 20° C. and diluted with water, decanted and extracted with ether. The extracts were dried and separated out by distillation to obtain 13 g of the expected product with a boiling point of 71° C. to 72° C. under 1 mmHg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[NH:13][C:12](=O)[C:11]=2[CH:10]=[CH:9]1.P(Cl)(Cl)([Cl:25])=O>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([Cl:25])[C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1-n1ccc2c(=O)[nH]c3c(C)cccc3c21
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccccc1-n1ccc2c(Cl)nc3c(C)cccc3c21

Procedure:
1-(2-Methylphenyl)-4-oxo-6-methyl-4,5-dihydropyrrolo[3,2-c]quinoline (4.75 g) and phosphoryl chloride (40 ml) were heated at reflux for 1.5 hours. The phosphoryl chloride was evaporated in vacuo, the residue poured onto ice and extracted with dichloromethane, which was dried and evaporated. Crystallisation from ethanol yielded 1-(2-methylphenyl)-4-chloro-6-methylpyrrolo[3,2-c]quinoline (4.76 g), m.p.135°-137°.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([C:26]1[S:27][C:28]([CH2:31][CH2:32][C:33]([OH:35])=O)=[CH:29][N:30]=1)[NH:5][C:6](=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[O:16])=[CH:10][CH:9]=1.CN(C=O)C.CCN=C=NCCCN(C)C.Cl.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56]>CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:54][S:55]([NH:58][C:33](=[O:35])[CH2:32][CH2:31][C:28]1[S:27][C:26]([CH:4]([NH:5][C:6](=[O:25])[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])=[O:16])=[CH:12][CH:13]=2)[CH2:3][CH:2]([CH3:36])[CH3:1])=[N:30][CH:29]=1)(=[O:57])=[O:56]
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)c2ncc(CCC(=O)O)s2)cc1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)c2ncc(CCC(=O)NS(C)(=O)=O)s2)cc1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
A mixture of 3-[2-(3methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-thiazol-5-yl]-propionic acid (Example 13) (91 mg, 0.2 mmol), DMF (5 ml), EDCl (48 mg, 0.2 mmol) and DMAP (26 mg, 0.2 mmol) was stirred at room temperature. After 10 min. methane sulfonamide (51 mg, 0.5 mmol) was added. After stirring 16 h the solution was diluted with EtOAc and washed with 1N HCl (2×). The organic layer was dried over Na2SO4; filtered; and concentrated under reduced pressure. The resulting solid was purified by Flash 12 chromatography eluting with 10% AcOH in EtOAc to give 30 mg of the title compound as a white amorphous solid. MS [M−1]+ 584.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[I:18].[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][O:19]1)[N:13]=[C:12]2[I:18]
Reactant: C1=COCCC1
Reactant: Fc1cccc(F)c1-c1ccc2[nH]nc(I)c2c1
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(F)c1-c1ccc2c(c1)c(I)nn2C1CCCCO1
Temperature: 70 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of 5-(2,6-difluoro-phenyl)-3-iodo-1H-indazole (45.5 g, 127.76 mmol) and TSA (4.86 g, 25.55 mmol) in THF (383.2 mL) was added 3,4-dihydro-2H-pyran (23.8 mL, 255.53 mmol) at RT. The mixture was stirred at 70° C. for 8 h. The reaction mixture was cooled to RT. Water was added to the reaction mixture and extracted with EtOAc (2×500 mL). The organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure. The crude product was purified by column using (100-200 mesh) silica with 0-5% EtOAc in hexane to provide 5-(2,6-difluoro-phenyl)-3-iodo-1-(tetrahydro-pyran-2-yl)-1H-indazole (42.95 g, 78.2% yield). MS (ESI, pos. ion) m/z: 441.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[C:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:3]1.[NH4+].[Cl-].[CH3:21]COCC>[Cu]Cl>[CH3:21][C:4]1([CH:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:3][C:2]([CH3:1])([CH3:18])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]1
Reactant: CCOCC
Reactant: CCOC(=O)C(C#N)=C1CC(C)(C)CC(C)(C)C1
Agent: Cl[Cu]
Agent: [Cl-]
Agent: [NH4+]
Product: CCOC(=O)C(C#N)C1(C)CC(C)(C)CC(C)(C)C1
Reaction time: 0.08 h
Yield: 47 %

Procedure:
Anhydrous copper (I) chloride (0.8 g, 8 mmol) was added to a cooled solution of alkylmagnesium iodide (prepared from magnesium (0.46 g, 19.2 mmol) and iodomethane (2.84 g, 20 mmol)) in ether (12 ml). The mixture was stirred in an inert atmosphere for 5 min and a solution of ethyl (3,3,5,5-tetramethylcyclohexylidene)cyanoacetate (16) (2 g, 8 mmol) in ether (10 ml), was added dropwise keeping the temperature below -1 5 C. After the addition of ketone was completed, the reaction mixture was stirred for 3 h and carefully neutralised with saturated aqueous NH4Cl solution. Traditional workup for Grignard reactions gave crude material which was separated on a silica gel column, eluting with a petroleum ether-ethyl acetate mixture (20:1) to give 1.0 g (47%) of 17 as an oil.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1.O>[C:13]([O:1][CH:2]1[O:10][C@H:9]([CH2:11][O:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:7]([O:8][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:5]([O:6][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:3]1[O:4][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(OC[C@H]1OC(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1

Procedure:
100 g of D-glucose (555 mmol; 1 eq) are dissolved in 2 l of pyridine and the reaction medium is heated under reflux for 1 hour before 387 ml (3,330 mmol; 6 eq) of benzoyl chloride are added thereto in the hot. After addition, the medium is diluted with water, the product precipitates and is filtered off and rinsed with water to neutrality. After drying, it is purified by recrystallisation from ethyl acetate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[Br:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:25]=[C:24]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=3)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.1) (0.59 g, 2.0 mmol) and commercially available 3-bromo-benzeneboronic acid (0.44 g, 2.20 mmol) according to the general procedure IVa. Obtained as a white solid (0.71 g, 86%). MS (EI) 413.9 [(M)+]; mp 146° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:15][CH3:16])[CH2:3][O:4][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[O:6].[CH2:17]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH2:15][CH3:16])[CH2:3][O:4][C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:37]([C:34]2[CH:33]=[CH:32][C:31]([C:28]3[CH:29]=[CH:30][C:25]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:26][CH:27]=3)=[CH:36][CH:35]=2)=[O:38])=[CH:12][CH:13]=1)=[O:6]
Reactant: CCCCCCCCc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: CCC(C)COC(=O)Oc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(OC(=O)OCC(C)CC)cc3)cc2)cc1
Temperature: 60 °C

Procedure:
p-(2-Methylbutyloxycarbonyloxy)phenol (0.25 g) prepared in the above (i) was dissolved in pyridine (5 ml) and cooled with ice, followed by dropwise adding a solution of 4'-octyl-4-biphenylcarboxylic acid chloride (0.37 g) dissolved in toluene (5 ml), heating on a water bath at 60° C., reacting the mixture, adding toluene (50 ml), separating the toluene layer, washing with 6N-hydrochloric acid, further with 2N-NaOH aqueous solution, then with a saturated NaCl aqueous solution to make the layer neutral, drying over sodium sulfate, concentrating, and twice recrystallizing from a mixed solution of ethyl acetate (20 ml) and ethanol (10 ml) to obtain the objective 4'-octyl-4-biphenylcarboxylic acid p-(2-methylbutyloxycarbonyloxy)phenyl ester. This product exhibited SA phase and Ch phase and its phase transition points, C-SA point, SA-Ch point, and Ch-I point were 78.3° C., 150.2° C. and 165.2° C., respectively. Further its values of elemental analysis accorded well with its calculated values as follows:
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])=[C:16]([CH:19]=1)[C:17]#[N:18].N1C=CC=CC=1>C(Cl)Cl>[C:17]([C:16]1[CH:19]=[C:12]([NH:11][C:8](=[O:9])[O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:14][C:15]=1[S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])#[N:18]
Reactant: CCS(=O)(=O)c1ccc(N)cc1C#N
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1C#N
Reaction time: 1 h
Yield: 85 %

Procedure:
Phenylchloroformate (0.63 mL, 5 mmol) was added dropwise to a solution of 6B in methylene chloride (10 mL) and pyridine (0.60 mL, 7.1 mmol) at 0° C. After stirring for 1 h, the reaction mixture was partitioned between 1.0 M HCl (150 mL) and EtOAc (150 mL). The layers were separated and the organic phase was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (0% to 100% EtOAc in hexanes) to yield 25A (1.34 g, 85%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.32 (t, J=7.45 Hz, 3 H) 3.36 (q, J=7.33 Hz, 2 H) 7.14-7.21 (m, J=7.58 Hz, 2 H) 7.26-7.31 (m, J=7.45, 7.45 Hz, 1 H) 7.37-7.45 (m, J=7.83, 7.83 Hz, 2 H) 7.66 (bs, 1 H) 7.83 (dd, J=8.72, 2.15 Hz, 1 H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].Cl.[CH3:13][C:14]1[S:15][CH:16]=[C:17]([C:19]([N:21]2[CH2:26][C:25]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[O:24][CH2:23][CH2:22]2)=[O:20])[N:18]=1>C(N(CC)CC)C.C(#N)C>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]1[CH2:30][CH2:31][C:25]2([O:24][CH2:23][CH2:22][N:21]([C:19]([C:17]3[N:18]=[C:14]([CH3:13])[S:15][CH:16]=3)=[O:20])[CH2:26]2)[CH2:27][CH2:28]1
Reactant: OCCCCCCCCCBr
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCCCCCCCCO)CC3)C2)cs1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
9-Bromononan-1-ol (0.29 g) was added to a suspension of (2-methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone hydrochloride (example 1, step f) (0.4 g) in a mixture of triethylamine (0.41 mL) and acetonitrile (10 mL). The resulting mixture was stirred for 16 h at 50° C. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (30 mL) and saturated sodium bicarbonate solution (30 mL). The layers were separated and the aqueous extracted with ethyl acetate (2×30 mL). The combined organic solutions were washed with brine (30 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in methanol (10 mL) and applied to a SCX cartridge pre-wetted with methanol. The cartridge was washed with methanol (10 mL) and eluted with 3M ammonia in methanol solution (100 mL). The eluent was evaporated in vacuo to give the subtitled compound a yellow oil. Yield 0.32 g.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][C:12](=[O:14])[C:11]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C([N:34](CC)CC)C.[CH:39]1[C:52]2C3[C:46](=[CH:47][CH:48]=CC=3)[CH2:45][NH:44][C:43]=2C=C[CH:40]=1>ClCCl.C(OCC)(=O)C>[C:20]1([C:21]([NH2:34])=[O:23])[C:19]2[C:18]3[C:46](=[CH:47][CH:48]=[CH:16][CH:17]=3)[CH2:45][NH:44][C:43]=2[CH:52]=[CH:39][CH:40]=1.[Si:1]([O:8][CH:9]1[CH2:13][C:12](=[O:14])[C:11]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: c1ccc2c(c1)CNc1ccccc1-2
Agent: CC(C)(C)[Si](C)(C)OC1C=C(SCCCCCC(=O)O)C(=O)C1
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)c1cccc2c1-c1ccccc1CN2
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
2.12 g (5.92 mmoles) of 4(RS)-t-butyldimethylsilyloxy-2-(5-carboxypentylthio)-2-cyclopentenone was dissolved in 30 ml of dichloromethane, and the solution was cooled to -40° C. To the solution were added 970 mg (920 microliters; 7.10 mmols) of isobutyl chloroformate and 896 mg (1.24 ml, 8.88 mmoles) of triethylamine were added, and the mixture was stirred at -40° C. for 30 minutes. Then, 10 ml of a dichloromethane solution of 1.29 g (7.10 mmoles) of 5,6-dihydrophenanthridine was added to the resulting mixture. The temperature was gradually raised to room temperature over 20 hours. After the reaction, ethyl acetate was added to the reaction mixture to perform extraction. The extract was washed with dilute hydrochloric acid, an aqueous solution of sodium bicarbonate and then an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The resulting crude product was chromatographed on a silica gel column using hexane/ethyl acetate (4/1) as an eluent to give 2.657 g (5.1 mmoles; yield 86%) of 4(RS)-t-butyldimethylsilyloxy-2-(5-carboxypentylthio)-2-cyclopentenone 5,6-dihydrophenanthridinamide.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:28][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: BrCCCCCCOCCCCCCc1ccccn1
Product: c1ccc(CNCCCCCCOCCCCCCc2ccccn2)cc1
Reaction time: 1 h

Procedure:
2-[6-[(6-Bromohexyl)oxy]hexyl]pyridine (4.99 g) was added dropwise to benzylamine (22 ml) at 140° C. under nitrogen. The solution was stirred at 140° for 1 h and distilled under vacuum to remove benzylamine. The residue was partitioned between ethyl acetate (300 ml) and 8% aqueous sodium bicarbonate (200 ml). The dried organic layer was concentrated and the residual oil was purified by FCC eluting with ethyl acetate-triethylamine (100:1) to give the title compound as a pale yellow oil (4.65 g), t.l.c. (ethyl acetate+few drops triethylamine) Rf 0.23.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15]1(OB(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[I:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Reactant: OB(O)Oc1ccccc1
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: Cc1ccccc1
Product: Ic1ccc(-c2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
The compound was prepared under Suzuki reaction conditions. 4,4′-diiodo-biphenyl (1.0 g, 2.46 mmol), phenyl boric acid (0.24 g, 1.970 mmol), tetrakis(triphenylphosphine)palladium (0.085 g, 0.074 mmol), 2M-sodium carbonate (12.3 ml) and toluene (76 ml) were simultaneously mixed, freezed under liquid nitrogen, evacuated by a vacuum pump and then warmed to room temperature to be melted. This procedure was repeated twice, followed by injection of nitrogen. The mixed solution was refluxed for 2 days and cooled to room temperature. Thereafter, a small amount of distilled water was added, and the organic layer was filtered three times with dichloromethane, dried with sodium sulfate. Then, the dichloromethane was concentrated under reduced pressure. Purification by silica gel chromatography using 1% dichloromethane in hexane gave 4″-iodo-[1,1′;4′,1″]terphenyl (Yield: 0.245 g, 35%). The structure of the product was identified through the NMR spectrum and mass spectrum. FIG. 6 shows the mass spectrum of 4″-iodo-[1,1′;4′,1″]terphenyl.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[C@H:9]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[C@H:8](OS(C)(=O)=O)[CH:7]=1)=[O:5])[CH3:2].CS(C)=O.[N-:31]=[N+:32]=[N-:33].[Na+]>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[C@@H:9]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[C@H:8]([N:31]=[N+:32]=[N-:33])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C[C@@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)[C@H](OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C[C@@H](N=[N+]=[N-])[C@H](OS(C)(=O)=O)[C@H](OS(C)(=O)=O)C1
Reaction time: 2.5 h
Yield: 70.5 %

Procedure:
A 5 mL round-bottom flask equipped with a magnetic stirrer and an inert gas supply was charged with 436.3 mg of 12 and 0.83 mL DMSO. To the clear colorless solution at RT was added 71.5 mg sodium azide and the reaction mixture was stirred for 2.5 h, then an additional 13.7 mg of sodium azide were added and stirring continued at RT for 19 h. The reaction mixture was diluted with 5 mL of EtOAc and extracted three times with a 1 M solution of NaHCO3. The organic phase was separated, dried (Na2SO4), filtered and evaporated at 20° C./140-10 mbar to obtain 0.33 g of the crude product as light yellow oil. The crude product was purified by SiO2 column chromatography eluting with a ½ mixture of EtOAc and n-hexane. The combined fractions were evaporated and dried on a rotary evaporator to obtain 0.27 g of 14 as a colorless oil