Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[C:17]=2[CH2:18][C:19](O)=[O:20])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH:29][CH2:30][CH3:31])=[CH:24][CH:23]=1>>[ClH:1].[CH2:30]([N:29]([CH2:28][C:25]1[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=1)[C:19](=[O:20])[CH2:18][C:17]1[N:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]2=[N:9][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:31]
Reactant: Cc1ccn2c(CC(=O)O)c(-c3ccc(Cl)cc3)nc2c1
Reactant: CCNCc1ccncc1
Product: CCN(Cc1ccncc1)C(=O)Cc1c(-c2ccc(Cl)cc2)nc2cc(C)ccn12
Product: Cl
Yield: 69.5 %

Procedure:
According to the method of Example 14, 2-(4-chlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetic acid and N-(4-pyridinylmethyl)ethylamine were used as raw materials for synthesis, yellow solid powder, yield 69.5%. m.p. 245-247° C., ESI-MS m/z: 420[M+H]+, 1H NMR(D2O, 400 MHz)δ: 0.95(t, 0.7H, J=7.00 Hz), 1.11(t, 2.3H, J=7.00 Hz), 2.38(s, 2.3H), 2.39(s, 0.7H), 3.27(q, 0.5H, J=7.00 Hz), 3.52(q, 1.5H, J=7.00 Hz), 4.06(s, 0.5H), 4.39(s, 1.5H), 4.66(s, 1.5H), 4.88(s, 0.5H), 7.16-7.28(m, 2H), 7.35-7.47(m, 4H), 7.50(s, 1H), 7.65-7.66(m, 1H), 8.14-8.26(m, 1H), 8.44-8.51(m, 2H).
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([CH2:41]Cl)=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:34]=2)[CH:31]=1.[NH:43]1[CH:47]=[N:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[N:44]1>>[CH3:51][O:50][C:48]([C:45]1[N:46]=[CH:47][N:43]([CH2:41][C:32]2[N:30]3[CH:31]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]3=[N:34][C:33]=2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:44]=1)=[O:49]
Reactant: COC(=O)c1nc[nH]n1
Reactant: ClCc1c(-c2ccccc2)nc2ccc(Cl)cn12
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: COC(=O)c1ncn(Cc2c(-c3ccccc3)nc3ccc(Cl)cn23)n1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 6-chloro-3-(chloromethyl)-2-phenylimidazo[1,2-a]pyridine hydrochloride and methyl 1H-1,2,4-triazole-3-carboxylate. The two isomers were separated by silica gel chromatography (eluted with 20% acetone/hexane to flush out the less polar isomer (44) and then flashed with 50% acetone to get the second compound off the column (45). Compound 44: m/e+ 368 for C18H15ClN5O2 [M+H]−; 1H-NMR (400 MHz, CDCl3) δ 8.35 (d, J=1.1 Hz, 1H), 7.98 (s, 1H), 7.76 (dd, J=1.4, 8.0 Hz, 2H), 7.61 (d, J=9.5 Hz, 1H), 7.42 (m, 3H), 7.24 (m, 1H), 6.17 (s, 2H), 3.97 (s, 3H) ppm; Compound 45: m/e+ 368 for C18H15ClN5O2 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 8.18 (d, J=1.1 Hz, 1H), 7.99 (s, 1H), 7.63 (m, 3H), 7.44 (m, 3H), 7.25 (m, 1H), 5.82 (s, 2H), 3.97 (s, 3H) ppm.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9](F)=[C:8]2[C:3]=1[CH:4]=[C:5]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[N:6]=[CH:7]2.[F:21][C:22]([F:36])([F:35])[O:23]C1C=C2C(C=C(O)N=C2)=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.CCN(CC)CC>C(Cl)Cl>[F:21][C:22]([F:36])([F:35])[O:23][C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[C:5]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[N:6]=[CH:7]2)=[CH:2][CH:11]=1
Reactant: Oc1cc2ccc(OC(F)(F)F)cc2cn1
Reactant: O=S(=O)(Oc1cc2c(Cl)ccc(F)c2cn1)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Oc1cc2ccc(OC(F)(F)F)cc2cn1)C(F)(F)F

Procedure:
By following the procedure for the preparation of trifluoromethanesulfonic acid 5-chloro-8-fluoroisoquinolin-3-yl ester, the title compound was prepared from 7-trifluoromethoxyisoquinolin-3-ol (0.98 g, 4.3 mmol), triflic anhydride (0.17 mL, 1.0 mmol), NEt3 (0.8 mL, 3.0 mmol) and CH2Cl2 (10 mL). 1H NMR (CDCl3, 300 MHz): δ=7.63 (s, 1H), 7.65 (d, J=6.0 Hz, 1H), 7.89 (s, 1H), 7.98 (d, J=9.0 Hz, 1H), 9.10 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:5]=1.[F:15][C:16]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:17]=1[NH2:18].N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:12])(=[O:11])[NH:18][C:17]2[C:16]([F:15])=[CH:22][C:21]([F:23])=[CH:20][C:19]=2[F:24])[CH:5]=1
Reactant: Nc1c(F)cc(F)cc1F
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(S(=O)(=O)Nc2c(F)cc(F)cc2F)c1

Procedure:
2.35 g (10 mmol) of 3-chlorosulfonylbenzoic acid methyl ester is suspended in 30 ml of dichloromethane with exclusion of moisture, the suspension is cooled to -5° C and at this temperature a solution of 1.47 g (10 mmol) of 2,4,6-trifluoroaniline and 1 ml of pyridine in 20 ml of dichloromethane is instilled. When the instillation is completed, it is allowed to come to room temperature and is stirred for 12 more hours. The resulting precipitate is suctioned off and extracted with ether. The ether extract and filtrate together are concentrated by evaporation and the residue is dissolved in dichloroethane and chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane. 2.8 g (8.12 mmol)= 81.2% of the theoretical yield is obtained as an amorphous product.
Reaction SMILES: [CH3:1][C:2]([CH:4]=[O:5])=[O:3].[OH2:6].O[CH2:8][C:9](=[O:11])[CH3:10]>C(OCC)(=O)C.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[OH:6][CH:8]([CH:4]([OH:5])[C:2](=[O:3])[CH3:1])[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)CO
Reactant: O
Reactant: CC(=O)C=O
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(=O)C(O)C(O)C(C)=O

Procedure:
A solution of methyl glyoxal 40% wt in water (9 g, 50 mmoles), zinc acetate (0.44 g) and hydroxy-acetone (7.4 g) in ethyl acetate (20 ml) were stirred during 40 h at 38/40° (pH of the reaction medium was around 4.5). At the end of the reaction (which can be checked by gas chromatography), the reaction mixture was extracted with ethyl acetate (3×50 ml). The organic phase was washed to neutral with brine (1×), dried over magnesium sulphate and concentrated under vacuum giving 6 g of the crude 3,4-dihydroxyhexane-2,5-dione who was Bulb-to-bulb distilled at 0.1 mbar and 120-150° to obtain 3.8 g of a mixture of the two 3,4-dihydroxyhexane-2,5-dione isomers.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH:20](C1C=CN=CC=1)=C.BrC1C=C2C(=CC=1)NC=C2.CI>CN(C)C=O.O>[CH3:20][N:3]1[C:11]2[C:6](=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: C=Cc1ccncc1
Reactant: C(=C/c1ccc2[nH]ccc2c1)\c1ccncc1
Agent: Brc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc2cc(/C=C/c3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium hydride, 60% dispersion in oil (0.57 g, 14 mmol) was added portionwise to a suspension of (E)-4-(indol-5-yl)ethenylpyridine (2.82 g, 12.8 mmol) [prepared from 4-vinylpyridine and 5-bromoindole by an analogous procedure to Example 16] in dimethylformamide (100 ml). The mixture was stirred at room temperature, under nitrogen, for 1.5 h to give a red solution which was then cooled to 0° C. and treated dropwise with methyl iodide (0.88 ml, 14 mmol). The reaction mixture was stirred at 0° C. under nitrogen for 10 min, allowed to warm to room temperature and stirred for a further 30 min. The resulting suspension was diluted with water (200 ml), the solid collected under suction, washed with 5% aqueous sodium sulfite solution then water and dried in vacuo to afford the title compound as a buff solid (3.07 g); δH (CDCl3) 3.81 (3H, s, N-CH3), 6.51 (1H, dd, J 3.1, 0.7 Hz, 3'-H), 6.98 (1H, d, J 16.3 Hz, CH=CH), 7.07 (1H, d, J 3.1 Hz, 2'-H), 7.31-7.51 (5H, m, CH=CH, ArH), 7.78 (1H, d, J 1.4 Hz, 4'-H), 8.55 (2H, m, 2-H, 6-H-1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][C@@H:19]4[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]4)=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1.[CH:26]([C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]([O:36][CH3:37])=[O:35])[CH2:30][CH2:29]1)=O.C(C1(C(OC)=O)CCC1)=O>>[OH:25][C@@H:22]1[CH2:23][CH2:24][C@H:19]([O:18][C:14]2[C:13]3[C:9]([O:8][CH2:7][CH:4]4[CH2:5][CH2:6][N:1]([CH2:26][C@H:28]5[CH2:29][CH2:30][C@H:31]([C:34]([O:36][CH3:37])=[O:35])[CH2:32][CH2:33]5)[CH2:2][CH2:3]4)=[N:10][O:11][C:12]=3[CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21]1
Reactant: COC(=O)[C@H]1CC[C@H](C=O)CC1
Reactant: O[C@H]1CC[C@@H](Oc2cccc3onc(OCC4CCNCC4)c23)CC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)[C@H]1CC[C@H](CN2CCC(COc3noc4cccc(O[C@H]5CC[C@@H](O)CC5)c34)CC2)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using cis-4-{[3-(piperidin-4-ylmethoxy)-1,2-benzisoxazol-4-yl]oxy}cyclohexanol (EXAMPLE 43, Step 2) and methyl trans-4-formylcyclohexanecarboxylate (JP 490-48639) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([I:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:23])[CH2:19][C:20]([CH3:22])=O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:25]([O:24][C:18](=[O:23])/[CH:19]=[C:20](/[NH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:17])=[CH:10][C:11]=1[I:16])\[CH3:22])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)c(I)c1
Reactant: CC(=O)CC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C/C(=C\C(=O)OCc1ccccc1)Nc1ccc(CNC(=O)OC(C)(C)C)cc1I
Yield: 100.5 %

Procedure:
To a solution of (4-amino-3-iodo-benzyl)-carbamic acid tert-butyl ester (3.5 g, 10 mmol) and benzyl acetoacetate (1.92 g, 10 mmol) in benzene (80 mL) was added p-toluenesulfonic acid (95 mg, 0.5 mmol). The mixture was heated at reflux overnight using a Dean Stark condenser. The mixture was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give 5.25 g (99%) of crude desired product as a light brown oil: MS(APCI+): m/z 523.1 (MH+). The compound was taken to Step D without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:17])[NH:5][C:6]2[CH2:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH:12]=1)#[N:2].[Cl-:18].[NH4+:19].N>>[ClH:18].[CH:12]1[C:11]2[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH2:8][CH2:7][C:6]=2[NH:5][C:4](=[O:17])[C:3]=1[C:1]([NH2:19])=[NH:2]
Reactant: [NH4+]
Reactant: N#Cc1cc2c([nH]c1=O)CCc1ccccc1-2
Reactant: [Cl-]
Agent: N
Product: Cl
Product: N=C(N)c1cc2c([nH]c1=O)CCc1ccccc1-2
Temperature: 80 °C

Procedure:
Add 2.10 gm of 2-cyano-5,6-dihydrobenzo[f]quinolin-3(4H)-one to 0.53 gm of ammonium chloride in liquid ammonia in a steel bomb. Heat the system to 80° C. for 24 hours. Cool the system to room temperature and remove the ammonia. Isolate 5,6-dihydrobenzo[f]quinolin-3(4H)-one-2-carboxamidine hydrochloride.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1.[CH3:12][O:13][C:14](=O)[O:15]C.Cl>O1CCCC1.CCCCCC>[CH3:3][C:4]1([CH3:11])[CH2:9][CH:8]([C:14]([O:13][CH3:12])=[O:15])[C:7](=[O:10])[CH2:6][CH2:5]1
Reactant: COC(=O)OC
Reactant: CC1(C)CCC(=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C1CC(C)(C)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of hexane-washed NaH (0.72 g, 60%, 18 mmol) in tetrahydrofuran (30 mL) was added a solution of 4,4-dimethylcyclohexanone (2.0 g, 15.6 mmol) in tetrahydrofuran (20 mL). The suspension was stirred at room temperature for 30 minutes. Then dimethylcarbonate (6.31 mL, 75 mmol) was added dropwise by syringe. The mixture was heated to reflux for four hours. The mixture was acidified with 5% HCl and extracted with dichloromethane (100 mL×3) and washed with water, brine, and dried over Na2SO4. After concentration, the crude product was loaded on a column and eluted with 10% ethyl acetate in hexane to give title compound.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][C:18](O)=[O:19].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:9][N:10]([C:18](=[O:19])[CH2:17][C:16]([O:22][CH2:23][CH3:24])=[O:21])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1OC1CNC1
Reactant: CCOC(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)CC(=O)N1CC(Oc2ccccc2C(C)(C)C)C1
Yield: 53.4 %

Procedure:
To a stirred solution of 3-(2-tert-butylphenoxy)azetidine (0.35 g, 1.70 mmol), ethyl hydrogen malonate (0.25 g, 1.87 mmol) in methylene chloride (20.0 mL) was added EDCI (0.36 g, 1.87 mmol) and HOBt (0.25 g, 1.87 mmol) at room temperature. After 16 h the reaction mixture was concentrated under reduced pressure, the resulting residue was partitioned between ethyl acetate and water and separated. The organic layer was washed with 10% sodium bicarbonate, saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 50:50 heptane/ethyl acetate) to provide ethyl 3-(3-(2-tert-butylphenoxy)azetidin-1-yl)-3-oxopropanoate (0.29 g, 53%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]=O.[CH2:12]([C:14]1[S:18][C:17]([CH3:19])=[N:16][N:15]=1)[CH3:13]>C(O)(=O)C.C(OC(=O)C)(=O)C.[Cl-].[Cl-].[Zn+2]>[CH2:12]([C:14]1[S:18][C:17]([CH:19]=[CH:10][C:3]2[N:2]([CH3:1])[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=2)=[N:16][N:15]=1)[CH3:13]
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Reactant: CCc1nnc(C)s1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCc1nnc(C=Cc2ncc([N+](=O)[O-])n2C)s1

Procedure:
A solution of 15.5 g of 1-methyl-5-nitroimidazole-2carboxaldehyde in 50 ml of acetic acid and 25 ml of acetic anhydride is added at reflux temperature over a period of 10 hours to 12.8 g of 5-ethyl-2-methyl-1,3,4-thiadiazole and 0.5 g of ZnCl2 which have been dissolved in 100 ml of acetic acid and 50 ml of acetic anhydride. The mixture is kept at reflux temperature for a further 20 hours and the solvent is then evaporated. The residue is washed with acetone and passed through a ready-to-use silica gel column (Type A of Messrs. Merck) and eluted with CHCl3 /CH3OH=98 : 2. 5.6 g of the abovementioned reaction product with a melting point of 165° C. is obtained; this corresponds to 21% of the theory.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C:10]1[C:20]([NH2:21])=[N:19][C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[CH:17][C:12]=2[CH:11]=1.[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[NH2:18][C:15]1[N:16]=[CH:17][C:12]2[CH:11]=[C:10]([C:3]3[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=3[Cl:1])[C:20]([NH:21][C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])=[N:19][C:13]=2[N:14]=1
Reactant: Nc1ncc2cc(-c3c(Cl)ccc(Cl)c3Cl)c(N)nc2n1
Reactant: CC(C)(C)N=C=O
Product: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1c(Cl)ccc(Cl)c1Cl

Procedure:
The procedure of Example 2 was followed to react 0.30 g of 6-(2,3,6-trichloro-phenyl)-pyrido[2,3-d]-pyrimidine-2,7-diamine from Example 85 with tert-butyl isocyanate (0.108 mL). The product is purified by medium pressure chromatography (MPLC) using silica gel and eluting with 1:1 CHCl3 :EtOAc to afford the title compound; mp 329-330° C., CIMS (1% ammonia in methane): m/z (relative intensity) 439 (MH+ -1, 3), 441 (MH+ +1, 3), 84 (100).
Reaction SMILES: [CH3:1][C:2]1([C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[CH:15](OCC)=[O:16].C[O-].[Na+]>C1C=CC=CC=1.C(Cl)Cl.CCOCC>[OH:16][CH:15]=[C:4]1[C:5](=[O:8])[CH:6]=[CH:7][C:2]([CH3:1])([C:9]#[C:10][Si:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3]1
Reactant: CCOC=O
Reactant: CC1(C#C[Si](C)(C)C)C=CC(=O)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC1(C#C[Si](C)(C)C)C=CC(=O)C(=CO)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a solution of 8 (139 mg, 0.67 mmol) in dry benzene (7.8 mL) were added ethyl formate (97%, 244 mg, 3.2 mmol) and sodium methoxide (176 mg, 3.3 mmol), successively. The mixture was stirred at room temperature for 1 h. The mixture was diluted with methylene chloride/ether (1:2, 40 mL). The mixture was washed with 5% aqueous HCl solution (15 mL×2). The acidic washings were extracted with methylene chloride/ether (1:2, 20 mL×1). The original organic solution and the extract were combined. The combined solution was washed with water (15 mL×2) and brine (15 mL×1), dried over MgSO4, and filtered. The filtrate was evaporate in vacuo to give 6-(hydroxymethylene)-4-methyl-4-((trimethylsilyl)-ethynyl)cyclohex-2-enone (148 mg, 94%): 1H NMR (CDCl3) δ 13.69 (1H, brs), 7.53 (1H, s), 6.64 (1H, d, J=9.9 Hz), 6.00 (1H, d, J=9.9 Hz), 2.78 (1H, d, J=14.6 Hz), 2.47 (1H, d, J=14.6 Hz), 1.38 (3H, s), 0.14 (9H, s); 13C NMR (CDCl3) δ 187.7, 168.0, 152.3, 126.8, 110.2, 109.5, 106.1, 37.2, 37.1, 26.9, 0.2. This material was used without further purification for the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:16]=[O:17].[BH4-].[Na+]>O.CO.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:16][OH:17])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)nc1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: OCc1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
To a toluene (300 mL) solution of 2,5-dibromopyridine (10.0 g, 42.2 mmol) was added dropwise n-butyl lithium (2.55 M n-hexane solution, 18.2 mL, 46.4 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 2 hours at −78° C. N,N-dimethylformamide (3.7 g, 50.6 mmol) was then added dropwise thereto and stirred for 10 minutes at −78° C. Sodium borohydride (3.20 g, 84.4 mmol) and methanol (20.0 mL) were then added and stirred for 30 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:1→2:1) to obtain the title compound (4.70 g, 59.2%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[CH:4]([CH2:21][OH:22])[NH:5][C:6](=[O:20])[C:7]1[C:12]([I:13])=[C:11]([NH2:14])[C:10]([I:15])=[C:9]([C:16]([OH:18])=[O:17])[C:8]=1[I:19].[CH3:24][C:25](N(C)C)=[O:26].C(Cl)(=O)C>O>[CH3:1][NH:2][C:3](=[O:23])[CH:4]([CH2:21][OH:22])[NH:5][C:6](=[O:20])[C:7]1[C:12]([I:13])=[C:11]([NH:14][C:25](=[O:26])[CH3:24])[C:10]([I:15])=[C:9]([C:16]([OH:18])=[O:17])[C:8]=1[I:19]
Reactant: CC(=O)N(C)C
Reactant: CNC(=O)C(CO)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: CC(=O)Cl
Solvent: O
Product: CNC(=O)C(CO)NC(=O)c1c(I)c(NC(C)=O)c(I)c(C(=O)O)c1I
Reaction time: 20 h

Procedure:
82.4 g. (0.125 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-DL-serine methylamide (IVb), m.p. 259°-260° C. (decomposition), is dissolved in 200 ml. of dimethylacetamide; under agitation, 33.4 ml. of acetyl chloride is added dropwise thereto. The reaction mixture is agitated for 20 hours, mixed with 40 ml. of water, and, after another 30 minutes of agitation, concentrated under vacuum. The residue is stirred overnight with 150 ml. of water, the precipitate is vacuum-filtered, stirred in 150 ml. of 1 N sodium hydroxide solution with the addition of 15 ml. of 37% strength sodium hydroxide solution and activated carbon for 2 hours, the activated carbon is removed, and the filtrate is brought to pH 1 with concentrated hydrochloric acid. After allowing the reaction mixture to stand overnight at 0° C., the precipitate is vacuum-filtered, washed with ice water, and dried under vacuum at 70° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:27])=[CH:8][C:9]=1[N:10]([C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:4].[BH4-].[Na+].CCCCCC.CCOC(C)=O.Cl>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:27])=[CH:8][C:9]=1[N:10]([C@H:11]1[CH2:12][CH2:13][C@H:14]([OH:17])[CH2:15][CH2:16]1)[C:18]([C@H:20]1[CH2:21][CH2:22][C@H:23]([CH3:26])[CH2:24][CH2:25]1)=[O:19])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reaction time: 0.25 h

Procedure:
To a cold (0° C.) solution of 5-bromo-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (5.9 g, 12.9 mmol) in 50 mL of MeOH under a N2 atmosphere, NaBH4 (250 mg, 6.4 mmol) is added portion wise (approx. 30 min). After the addition is completed and checked for reaction completion by TLC (hexane:EtOAc 1:1), 10 mL of HCl 2% is added and stirred for 15 min. The reaction mixture is concentrated under vacuum to dryness. The reaction mixture is recuperated with water (25 mL) and extracted with EtOAC. The organic phases are combined and dried over MgSO4 and concentrated to dryness. The residue is purified by silica gel column chromatography using EtOAc:hexane (1:1) as eluent to obtain 5-bromo-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (4.5 g, 77% yield) as a solid.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:19]1[CH:20]=[C:21]([C:26]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:27]=2)[CH:22]=[C:23](Br)[CH:24]=1.C([O-])([O-])=O.[K+].[K+].[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([C:56]2[CH:57]=[C:58](B(O)O)[CH:59]=[CH:60][CH:61]=2)[CH:51]=1>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.C(O)C.C1(C)C=CC=CC=1>[C:32]1([C:30]2[N:29]=[C:28]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:27]=[C:26]([C:21]3[CH:20]=[C:19]([C:58]4[CH:59]=[CH:60][CH:61]=[C:56]([C:52]5[CH:51]=[N:50][CH:55]=[CH:54][CH:53]=5)[CH:57]=4)[CH:24]=[C:23]([C:13]4[C:14]5[C:5]([C:6]6[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=6[CH:12]=4)=[CH:4][CH:3]=[CH:2][CH:1]=5)[CH:22]=3)[N:31]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Brc1cc(Br)cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Reactant: OB(O)c1cccc(-c2cccnc2)c1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3cc(-c4cccc(-c5cccnc5)c4)cc(-c4cc5ccccc5c5ccccc45)c3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
In a stream of argon, 0.71 g (3.21 mmol) of 9-phenanthreneboronic acid, 1.50 g (3.21 mmol) of 2-(3,5-dibromophenyl)-4,6-diphenyl-1,3,5-triazine and 37.0 mg (0.0321 mmol) of tetrakis(triphenylphosphine)palladium were suspended in a mixed solvent composed of 120 mL of toluene and 15 mL of ethanol, and the resultant suspension was heated to 60° C. To the suspension, 9.63 mL (9.63 mmol) of an aqueous 1M K2CO3 solution was gradually added dropwise, and the mixture was stirred for 8 hours. Then the mixture was cooled to room temperature, and 0.59 g (4.82 mmol) of 3-(3-pyridyl)phenylboronic acid and 9.63 mL (9.63 mmol) of an aqueous 1M K2CO3 solution were added. Then the mixture was heated to 60° C. and maintained at that temperature for 18 hours while being stirred. Then the reaction mixture was cooled to room temperature, and was then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The obtained crude product was purified by silica gel chromatography using a hexane/chloroform (1:2) mixed solvent as an eluent to give 0.86 g of the target 4,6-diphenyl-2-[5-(9-phenanthryl)-3′-(3-pyridyl)biphenyl-3-yl]-1,3,5-triazine as a white solid (yield: 42%).