Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH:16]=O.[C:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])#[N:26].N1CCCCC1>C(O)C.O>[CH2:31]([O:30][C:28]([C:27]1[CH:16]([C:15]2[CH:18]=[C:19]([O:23][CH3:24])[C:20]([O:21][CH3:22])=[C:13]([Br:12])[CH:14]=2)[C:2]2[C:1](=[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=2)[O:11][C:25]=1[NH2:26])=[O:29])[CH3:32]
Reactant: CCOC(=O)CC#N
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: Oc1cccc2ccccc12
Solvent: O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(N)Oc2c(ccc3ccccc23)C1c1cc(Br)c(OC)c(OC)c1
Temperature: 80 °C

Procedure:
1-Naphthol (170 mg, 1.2 mmol), 3-bromo-4,5-dimethoxybenzaldehyde (245 mg, 1 mmol) and ethyl cyanoacetate (113 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 μl) and then stirred at 80° C. under LC-MS control till the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with water to about 15 ml and stirred for 1 h at room temperature. The solids were collected by filtration, washed well with 60% aq. ethanol and dried under high vacuum (420 mg, 0.86 mmol, 86%).
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[N:22]=[CH:21][N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:18].[Cl:25][C:23]1[N:22]=[CH:21][N:20]=[C:19]([N:10]2[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=[C:9]2/[CH:1]=[CH:2]/[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:24]=1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Clc1cc(-n2c(/C=C/c3ccccc3)nc3ccccc32)ncn1

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 4,6-dichloropyrimidine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate-hexane to give the titled compound. MW: 376.33; mp: 203.0-204.0° C.; 1H-NMR (DMSO) δ: 9.27 (1H, d, J=1.1 Hz), 8.15 (1H, d, J=1.1 Hz), 8.02-7.94 (1H, m), 7.80-7.72 (4H, m), 7.49-7.27 (6H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:12][CH2:13][CH2:14][CH3:15])=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][NH:7][CH3:8].[CH3:16][C:17]1([CH3:33])[O:22][C:21]2[CH:23]=[C:24]([CH:27]=[CH:28][C:29]([OH:31])=O)[CH:25]=[N:26][C:20]=2[NH:19][C:18]1=[O:32].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:33][C:17]1([CH3:16])[O:22][C:21]2[CH:23]=[C:24](/[CH:27]=[CH:28]/[C:29]([N:7]([CH2:6][C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[C:4]=3[O:12][CH2:13][CH2:14][CH3:15])[CH3:8])=[O:31])[CH:25]=[N:26][C:20]=2[NH:19][C:18]1=[O:32]
Reactant: CC1(C)Oc2cc(C=CC(=O)O)cnc2NC1=O
Reactant: CCCOc1c(CNC)cccc1OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OC(C)(C)C(=O)N3)cccc1OC
Reaction time: 0.08 h
Yield: 74.6 %

Procedure:
To a solution of (3-methoxy-2-propoxy-benzyl)-methyl-amine (115 mg, 0.55 mmol) in DMF (5 mL) were added in sequential order 3-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-acrylic acid (181 mg, 0.5 mmol), 1-hydroxybenzotriazole (74 mg, 0.55 mmol), diisopropylethylamine (261 uL, 1.5 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (110 mg, 0.55 mmol). The reaction was placed in a microwave at 130° C. for 5 min. The solution was cooled in an ice bath and water was added with rapid stirring. The precipitate was filtered, dried and triturated with diethyl ether to yield the title compound (164 mg, 75%) as a white solid and as a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 11.37-11.39 (m, 1H), 8.14-8.18 (m, 1H), 7.87-7.93 (m, 1H), 7.47-7.53 (m, 1H), 7.27-7.34 (m, 1H), 6.92-7.09 (m, 3H), 6.60-6.66 (m, 1H), 4.62-4.79 (m, 2H), 3.84-3.90 (m, 2H), 3.78 (s, 3H), 2.88-3.09 (m, 3H), 1.70-1.74 (m, 2H), 1.40-1.49 (m 6H), 0.93-0.99 (m, 3H); MS (ESI) m/e 440 (C24H29N3O5+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH2:37][CH3:38])=[C:10](\[C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([OH:36])=O)=[CH:28][CH:27]=1)/[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[N:15]=[CH:14]2.C(Cl)(=O)C([Cl:42])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH2:37][CH3:38])=[C:10](\[C:26]1[CH:27]=[CH:28][C:29](/[CH:32]=[CH:33]/[C:34]([Cl:42])=[O:36])=[CH:30][CH:31]=1)/[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[N:15]=[CH:14]2
Reactant: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccc(F)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC/C(=C(/c1ccc(/C=C/C(=O)Cl)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (1 g, 1.88 mmol; Compound 407) in DCM (9.4 mL) at room temperature, oxalyl dichloride (0.33 mL, 3.76 mmol) was added. After the addition of DMF (2 drops), the mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated to afford a pale yellow solid. This material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:16][C:17]([N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[O:18])[S:10][N:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:34]1([CH3:43])[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1>CN(C)C=O.CCOC(C)=O>[CH3:43][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:16][C:17]([N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])=[O:18])[S:10][N:9]=3)=[CH:6][CH:7]=2)=[O:42])=[CH:36][CH:35]=1
Reactant: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)N1CCCC1=O
Reactant: Cc1ccc(N=C=O)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)Nc2ccc(-c3nsc(NC(=O)N4CCCC4=O)c3C(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A solution of 3-(4-aminophenyl)-5-{[(2-oxopyrrolidin-1-yl)carbonyl]amino}isothiazole-4-carboxamide (9.6 g, 0.027 mol), diisopropylethylamine (5.3 g, 0.046 mol) in dimethylformamide (150 mL) at ambient temperature was treated with para-Tolyl isocyanate (4.0 g 0.03 mol) over 20 minute period. The resulting mixture was stirred at ambient temperature for 2 hr. The reaction mixture was concentrated in vacuo to give an off white solid, which was stirred in EtOAc (150 mL), filtered the solid and washed with EtOAc to give the title compound as a white solid (11.8 g, 88%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:22])[CH2:13][CH2:12][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:14]#[N:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH:26]1[CH2:28][CH2:27]1.[H-].[Na+].O>CN(C=O)C>[CH:26]1([CH2:25][CH2:24][O:22][C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:13][CH2:12][C:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:14]#[N:15])[CH2:10][CH2:9]2)[CH2:28][CH2:27]1
Reactant: BrCCC1CC1
Reactant: N#CC1(c2ccccc2)CCC(O)(c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(c2ccccc2)CCC(OCCC2CC2)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 47.1 %

Procedure:
500 mg of the compound of Example 1, 760 mg of (2-bromoethyl)cyclopropane (Chorvat et al., J. Med. Chem. 28, 194-200 (1985)) and 122 mg of sodium hydride in 20 ml of anhydrous DMF were stirred at room temperature for 19 h. 760 mg of (2-bromoethyl)cyclopropane and 122 mg of sodium hydride were then added and the mixture was stirred at room temperature for 4 days. The reaction mixture was then treated with 100 ml of water and extracted three times with 50 ml each of EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. 290 mg of the title compound were obtained as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](OCCCCCCCC)=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:18]=1.[Br:32][C:33]1[CH:45]=[CH:44][C:43]2[C:42]3[C:37](=[CH:38][C:39]([Br:46])=[CH:40][CH:41]=3)[C:36](=[O:47])[C:35]=2[CH:34]=1.[OH2:48]>C1COCC1.[Cl-].[Na+].O>[CH2:24]([O:23][C:19]1[CH:20]=[CH:21][C:22]([C:36]2([OH:47])[C:35]3[CH:34]=[C:33]([Br:32])[CH:45]=[CH:44][C:43]=3[C:42]3[C:37]2=[CH:38][C:39]([Br:46])=[CH:40][CH:41]=3)=[C:17]([C:3]2[CH:4]=[CH:5][C:6]([O:48][CH2:6][CH2:7][CH2:2][CH2:3][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:7][CH:2]=2)[CH:18]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCOc1cccc(-c2cc(OCCCCCCCC)ccc2Br)c1
Reactant: O
Reactant: O=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2cc(OCCCCCCCC)ccc2C2(O)c3cc(Br)ccc3-c3ccc(Br)cc32)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2-bromo-5,3′-bis-octyloxy-biphenyl (0.598 g, 1.225 mmol) prepared in Example 3 was dissolved in dried THF (30 ml) and cooled to −78° C. Then, 5-butyllithium (t-BuLi) (1.7M, 1.44 ml, 2.45 mmol) was added slowly. The obtained resultant was stirred for about 1 hour at −78° C. After 1 hour, 2,7-dibromofluorene-9-on (0.497 g, 1.47 mmol) dissolved in dried THF (20 ml) was added slowly, stirred for about 1 hour, allowed to warm to room temperature and further stirred at room temperature for about 30 minutes. A small amount of distilled water was added to complete the reaction and saturated brine was added to the resultant. The organic layer was filtered twice with ether and dried over sulfate, and the ether was concentrated under reduced pressure. Purification by silica gel chromatography using 30 to 40% dichloromethane in hexane gave 9-(5,4′-bis-octyloxy-biphenyl-2-yl)-2,7-dibromo-9H-fluorene-9-ol corresponding to the compound IV of the reaction scheme 1 (Yield: 0.62 g, 68%), R1 and R2 in the formula of the compound IV being each independently octyl and X being boron. The product was identified through the NMR spectrum and element analysis that it had the identical structure with the compound IV.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[C:4]([O:12][CH:13]([CH:16]2[CH2:18][CH2:17]2)[C:14]#[CH:15])[CH:3]=1.C(N(CC)C1C=CC=CC=1)C.Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[C:4]2[C:3]=1[CH:15]=[CH:14][CH:13]([CH:16]1[CH2:18][CH2:17]1)[O:12]2
Reactant: C#CC(Oc1cc(Br)ccc1OC(F)F)C1CC1
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Solvent: O
Product: FC(F)Oc1ccc(Br)c2c1OC(C1CC1)C=C2
Temperature: 200 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
To 545 mg (1.7 mmol) of 4-bromo-2-(1-cyclopropyl-2-propynyloxy)-1-difluoromethoxybenzene obtained in Reference example 14-(b) was added 5 ml of N,N-diethylaniline, and the mixture was stirred at 200° C. for 2 hours. After completion of the reaction, water was added to the reaction mixture, and then, a pH of the mixture was adjusted to 1 with conc. hydrochloric acid, and the mixture was extracted with diethyl ether. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 339 mg of the title compound as yellowish liquid. (Yield: 63%)
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH2:27][CH2:28][O:29][CH3:30])[CH2:21][C:22]#[C:23][C:24]([OH:26])=O.[Br:31][C:32]1[CH:33]=[C:34]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46]([NH2:49])[CH:47]=3)[N:42]=[CH:41][N:40]=2)[CH:35]=[CH:36][CH:37]=1>O1CCCC1.N1C=CC=CC=1>[Br:31][C:32]1[CH:33]=[C:34]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46]([NH:49][C:24](=[O:26])[C:23]#[C:22][CH2:21][N:20]([CH2:19][CH2:18][O:17][CH3:16])[CH2:27][CH2:28][O:29][CH3:30])[CH:47]=3)[N:42]=[CH:41][N:40]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: COCCN(CC#CC(=O)O)CCOC
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: COCCN(CC#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1)CCOC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.1 %

Procedure:
Isobutyl chloroformate (0.845 g, 6.2 mmol) and N-methylmorpholine (0.963 g, 9.52 mmol) were added to an ice cold solution of 2.100 g (9.52 mmol) of 4-[bis-(2-methoxy-ethyl)-amino]-but-2-ynoic acid in 50 mL of tetrahydrofuran under nitrogen. After stirring for 30 min, a solution of 1.500 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 10 mL of pyridine was added and the mixture was stirred for 2 hr at 0° C. The reaction was then quenched with ice water, poured into saturated sodium bicarbonate, and the product was extracted with ethyl acetate. Chromatography of the extract on silica gel, eluting with methanol/ethyl acetate (15:85), gave 0.660 g of 4-[Bis-(2-methoxy-ethyl)-amino]-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide: mass spectrum (m/e): M+H 512.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]1[C:17]2[S:28][C:27]([C:29]([O:31][CH3:32])=[O:30])=[CH:26][C:18]=2[N:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:20]=1>C(Cl)Cl>[Br:1][C:20]1[N:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:18]2[CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[S:28][C:17]=2[C:16]=1[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[F:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cn1cc(C2CCCCC2F)c2sc(C(=O)OC)cc21
Solvent: ClCCl
Product: COC(=O)Cn1c(Br)c(C2CCCCC2F)c2sc(C(=O)OC)cc21
Reaction time: 1 h
Yield: 100 %

Procedure:
N-bromo succinimide (1.5 eq.) was added at 0° C. to a 0.1M solution of methyl 6-(2-fluorocyclohexyl)-4-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate in dry DCM, and the mixture was stirred for 1 h. After dilution with EtOAc, the organic layer was washed with aq. Na2S2O3-solution and brine, dried over Na2SO4 and concentrated i. vac. Yield: 100%. 1H-NMR (300 MHz, CDCl3, 300 K, δ) 7.58 (s, 1H), 4.88 (d, 1H, J 17.9), 4.79 (d, 1H, J 17.9), 4.64 (dtd, 1H, J 49.3, 10.6, 4.4), 3.88 (s, 3H), 3.78 (s, 3H), 2.94-2.83 (m, 1H), 2.28-2.24 (m, 1H), 1.99-1.33 (m, 7H); MS (ES+) m/z 432, 434 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](C)=[CH:15][CH2:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN(C1C=CC2N=C3C(=CC(C=C3)=[N+](C)C)SC=2C=1)C.[C:39]1(=[O:45])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.[O:46]1[CH2:51]CCOO1>CC#N.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:14]=[CH:15][CH:16]3[CH2:51][O:46][C:39]4([CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)[O:45][O:17]3)=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: C1COOOC1
Reactant: CC(=CCO)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: O=C1CCCCC1
Agent: CN(C)c1ccc2nc3ccc(=[N+](C)C)cc-3sc2c1
Agent: Cl
Solvent: CC#N
Product: Clc1ccc(-c2ccc(C=CC3COC4(CCCCC4)OO3)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50 %

Procedure:
A solution of 3-[(4′-chloro-[1,1′-biphenyl]-4-yl)-2-butenol (4g, 500 mg) and methylene blue (40 mg) in CH3CN (30 ml) was photooxygenated at 5° C. for 5 h. Cyclohexanone (0.5 ml) and hydrochloric acid (5 drops) were added and reaction mixture was stirred at r.t. for 1.5 h and then left at r.t for 24 h. The reaction mixture was concentrated. Crude product was purified by column chromatography to furnish 360 mg (50% yield, based on allylic alcohol 4g, used) of trioxane 7gb, m.p. 109-111° C.
Reaction SMILES: [C:1]1([S:7]([O:9][Na])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N#N.Cl>O>[C:1]1([S:7]([OH:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(O[Na])c1ccccc1
Agent: Cl
Agent: N#N
Solvent: O
Product: O=S(O)c1ccccc1

Procedure:
PhSO2Na (1.6579 g., 0.0101 mol) was dissolved in water (100 mL), while keeping an atmosphere of N2. HCl (12 M, 0.84 mL, 0.0101 mol). was added in order to produce PhSO2H. Benzoquinone (0.01 mol, 1.081 g) was added while flushing with N2. A white to grey precipitate was formed immediately. The solution was stirred for 5 min, filtered (glass sinter no. 3) under N2, washed with distilled water (20 mL) and dried under vacuum (+20C) over night. Yield 2.08 g. The product was identified by 1H- and 13CNMR spectroscopy.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([OH:13])[C:7]=1[CH2:14][CH2:15][CH:16]1[O:21][C:20](=[O:22])[CH2:19][CH:18]([OH:23])[CH2:17]1.N1C=CC=CC=1>CCOCC>[C:1]([O:13][C:8]1[CH:9]=[C:10]([Cl:12])[CH:11]=[C:6]([Cl:5])[C:7]=1[CH2:14][CH2:15][CH:16]1[O:21][C:20](=[O:22])[CH2:19][CH:18]([OH:23])[CH2:17]1)(=[O:3])[CH3:2]
Reactant: O=C1CC(O)CC(CCc2c(O)cc(Cl)cc2Cl)O1
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(Cl)cc(Cl)c1CCC1CC(O)CC(=O)O1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (0.08 ml, 1.05 mmole) was added dropwise to a stirred solution of 6-[2-(2,4-dichloro-6-hydroxyphenyl)ethyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (300 mg, 1 mmole) and pyridine (0.09 ml, 1.05 mmole) in ether (10 ml) at 0° C. The ice bath was removed and the reaction mixture was stirred at 20° C. for 1 hour and then diluted with H2O (10 ml). The organic layer was separated and washed with 1N HCl (10 ml), H2O (2×10 ml) and brine, dried over MgSO4, filtered and evaporated to provide the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]=1[Cl:11])=[O:5])C.[OH-].[Li+].CO.Cl>O1CCCC1.O>[Cl:11][C:10]1[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn(-c2ccccc2)c1Cl
Temperature: 70 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate 1; 7.3 g, 29.1 mmol) in tetrahydrofuran (70 mL) was added a solution of lithium hydroxide in water (7.3 g, 305 mmol) in water (70 mL). Methanol (˜10 mL) was added dropwise to the reaction mixture until only one layer was visible. The reaction mixture was stirred at 70° C. for 1 hour (reaction progress monitored by TLC). The reaction mixture was acidified to pH 3 with 1N hydrochloric acid and washed with dichloromethane (3×200 mL). The organic layer was dried over magnesium sulfate and evaporated to give 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (5.8 g, 91%), which HPLC analysis indicated was 85% pure. This material was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]=[O:9])=[C:6]([NH2:10])[N:5]=[C:4](SC)[N:3]=1.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH2:20][NH2:21])=[CH:17][CH:16]=1>O>[NH2:1][C:2]1[C:7]([N:8]=[O:9])=[C:6]([NH2:10])[N:5]=[C:4]([NH:21][CH2:20][CH2:19][C:18]2[CH:22]=[CH:23][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1ccc(CCN)cc1
Reactant: CSc1nc(N)c(N=O)c(N)n1
Solvent: O
Product: COc1ccc(CCNc2nc(N)c(N=O)c(N)n2)cc1
Yield: 84 %

Procedure:
The starting material was prepared as follows:-1) A mixture of 4,6-diamino-2-methylthio-5-nitrosopyrimidine (10 g, 5.4 mM), 4-methoxyphenethylamine (7.92 ml, 5.4 mM) and water (180 ml) was heated to reflux for one hour. After cooling the red solid was separated by filtration, washed with water, and dried. There was thus obtained 4,6-diamino-2-[2-(4-methoxyphenyl)-ethyl]amino-5-nitrosopyrimidine (13.4 g, 84% yield). NMR: DMSO-d6 ; 2.7-2.85(m,2H, CH2 --CH2), 3.4-3.6(m, 2H, CH2 --NH), 3.7 (s, 3H, OCH3), 6.75-6.8(m,2H, aromatic-H), 7.05-7.25 (m, 2H, aromatic-H), 7.4-10.5 (m,5H, NH2 ×2, NH), m/e [M+H[+ 289.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3.[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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>[F:16][C:9]1[CH:8]=[C:7]2[C:12]([N:13]=[C:14]([CH3:15])[C:5]3[N:6]2[C:2]([C:20]2[S:21][CH:22]=[CH:23][C:19]=2[CH3:18])=[N:3][C:4]=3[CH3:17])=[CH:11][CH:10]=1
Reactant: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
Reactant: Cc1ccsc1B(O)O
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+]
Product: Cc1ccsc1-c1nc(C)c2c(C)nc3ccc(F)cc3n12
Yield: 100.2 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 5A (75 mg, 0.25 mmol), 3-methyl-2-thienylboronic acid (178 mg, 1.25 mmol), K2CO3 (105 mg, 0.75 mmol) and Pd(PPh3)4 (5.8 mg, 0.005 mmol) provided the coupling product as a white powder (78 mg, 100% yield). EIMS 312.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Temperature: 90 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
A mixture of 5-bromo-2-fluorobenzonitrile (25.0 g, 125 mmol), 4-methylimidazole (12.5 g, 152 mmol), potassium carbonate (34.55 g, 250 mmol) in DMSO (500 mL) was stirred at 90° C. for 16 h. Water (1.5 L) was added and the resulting suspension was stirred with ice-bath cooling for 1 h. The precipitate was then filtered off, washed with water (0.5 L) and dried at 50° C. over KOH. The resulting raw material (25.6 g) was dissolved in boiling ethyl acetate (300 mL). After addition of diisopropylether (300 mL) the solution was allowed to cool to room temperature. Filtration and drying afforded the title compound (19.35 g, 59%) as a white solid. Mp 166° C.
Reaction SMILES: [CH3:1][C:2]1[S:23][C:5]2=[N:6][C:7]([CH3:22])=[C:8]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:4]2[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:34]1[CH2:38]OC[CH2:35]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[S:23][C:5]2=[N:6][C:7]([CH3:22])=[C:8]([CH:17]([CH2:35][CH2:34][CH3:38])[C:18]([O:20][CH3:21])=[O:19])[C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[C:4]2[CH:3]=1
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc(C)cc2c1-c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc(C)cc2c1-c1ccc(C)cc1
Yield: 65.4 %

Procedure:
This compound was prepared according to the procedure C from methyl 2-(2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.188 g; 0.578 mmol), LHMDS 1N in THF (0.650 mL; 0.650 mmol), 1-iodopropane (0.092 mL; 0.943 mmol) in DMF (8 mL) for 4 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.139 g (65%) of the title compound as a yellow oil.