Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[N:23][NH:24][C:17]=34)[C:12]([CH3:25])=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[N:26]([CH2:29][CH3:30])=[C:27]=[O:28]>N1C=CC=CC=1.C(#N)C>[CH2:29]([NH:26][C:27]([N:24]1[C:17]2[C:18](=[N:19][CH:20]=[CH:21][C:16]=2[NH:15][C:13]2[C:12]([CH3:25])=[CH:11][N:10]=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=3)[CH:14]=2)[CH:22]=[N:23]1)=[O:28])[CH3:30]
Reactant: CCN=C=O
Reactant: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn[nH]c34)c(C)cn2)n1
Solvent: CC#N
Solvent: c1ccncc1
Product: CCNC(=O)n1ncc2nccc(Nc3cc(-c4nc(C)ccc4F)ncc3C)c21
Temperature: 75 °C

Procedure:
N-(3′-Fluoro-5,6′-dimethyl-2,2′-bipyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (81 mg, 0.242 mmol) was combined with acetonitrile (2.4 mL) and isocyanatoethane (23.78 μl, 0.303 mmol) along with 1 drop of pyridine. The mixture was heated at 75° C. The reaction was then cooled to give a solid which was collected by filtration, rinsed with acetonitrile to give the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (3H, t, J=7.20 Hz) 2.47 (3H, s) 2.64 (3H, s) 3.51-3.63 (2H, m) 7.17-7.23 (1H, m) 7.33 (1H, d, J=4.55 Hz) 7.43 (1H, dd, J=10.48, 8.46 Hz) 7.51-7.59 (1H, m) 8.08 (1H, br. s.) 8.27 (1H, s) 8.41 (1H, d, J=5.31 Hz) 8.65 (1H, br. s.) 11.00 (1H, br. s.). MS [M+H] found 406.4.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)(=[O:3])[CH3:2].[NH2:12][C@@H:13]([CH3:30])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[C:21]=2[CH3:29])=[N:16]1>>[C:1]([C:4]1[O:5][CH:6]=[C:7]([C:9]([NH:12][C@@H:13]([CH3:30])[CH2:14][N:15]2[CH:19]=[CH:18][C:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[C:21]=3[CH3:29])=[N:16]2)=[O:11])[N:8]=1)(=[O:3])[CH3:2]
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Reactant: CC(=O)c1nc(C(=O)O)co1
Product: CC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)co1
Yield: 12.47 %

Procedure:
(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-acetyloxazole-4-carboxylic acid (372 mg, 2.400 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (549 mg, 2.000 mmol). The product was triturated using diethyl ether and purified by Flash-chromatography, respectively. Yield 12.47%. 1H-NMR (400 MHz; CDCl3): δ 1.27 (d, 3H), 2.59 (s, 3H), 2.60 (s, 3H), 4.31 (dd, 1H), 4.45 (dd, 1H), 4.64 (m, 1H), 6.45 (d, 1H), 7.51 (d, 1H), 7.56 (m, 2H), 7.68 (d, 1H), 8.31 (s, 1H).
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:16]([S-:18])#[N:17].[K+].BrBr.O>CC(O)=O>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]2[N:13]=[C:16]([NH2:17])[S:18][C:14]=2[CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: N#C[S-]
Reactant: CCCCCCCCc1ccc(N)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCc1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
4-octylaniline (500 mg, 2.5 mmol), AcOH (4 mL), and KSCN (970 mg, 10 mmol) were stirred at r.t. for 10 min, and then a solution of bromine (0.13 mL, 2.5 mmol) in AcOH (2 mL) was added to the mixture over 20 min. The reaction mixture was stirred at r.t. for 8 h, then poured into cold water and extracted with EtOAc. The organic layer was purified by silica gel chromatography using PE/EA (3/1) to give compound the title compound (460 mg, 70%). 1H NMR (300 MHz, CDCl3) δ 7.446 (s, 1H), 7.320 (s, 1H), 7.230 (d, 1H), 2.577 (t, 2H), 1.567-1.506 (m, 2H), 1.266-1.167 (m, 10H), 0.847 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[F:18][C:19]1[C:27]([F:28])=[C:26]([F:29])[C:25]([F:30])=[C:24]2[C:20]=1[C:21]([CH:31]=O)=[CH:22][NH:23]2.[BH4-].[Na+]>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([NH:1][CH2:31][C:21]3[C:20]4[C:24](=[C:25]([F:30])[C:26]([F:29])=[C:27]([F:28])[C:19]=4[F:18])[NH:23][CH:22]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1c[nH]c2c(F)c(F)c(F)c(F)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1NCc1c[nH]c2c(F)c(F)c(F)c(F)c12

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide (100 mg) was then suspended in EtOH (4 mL) and 4,5,6,7-tetrafluoro-1H-indole-3-carbaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr. Resulting imine was suspended in 5 mL MeOH and sodium borohydride (3 eq.) was added. HPLC confirmed reaction was complete (absence of imine). After completion (1 hr), precipitate was filtered to obtain D22 as a light yellow powder as product. Product was washed with deionized water to remove excess sodium borohydride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([CH:56]=[CH:57][C:58]=1[CH3:59])[C:45]([NH:47][CH2:48][CH2:49][C:50]1[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=1)=[O:46]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:57]5[CH:56]=[C:44]([CH:43]=[CH:42][C:58]=5[CH3:59])[C:45]([NH:47][CH2:48][CH2:49][C:50]5[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=5)=[O:46])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Cc1ccc(C(=O)NCCc2cccnc2)cc1Br
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cc(C(=O)NCCc4cccnc4)ccc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (70 mg) and 3-bromo-4-methyl-N-(2-pyridin-3-yl-ethyl)-benzamide (62 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-methyl-N-(2-pyridin-3-yl-ethyl)-benzamide was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-304) as a pale brown powder (22 mg, 32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35].O>CN(C)C=O>[CH2:34]([N:36]([CH2:37][CH3:38])[CH2:17][CH:15]([OH:16])[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1])[CH3:35]
Reactant: CCNCC
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC1CO1
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CC(O)COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccccc3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (39 mg) and diethylamine (19 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (21 mg, yield 46%).
Reaction SMILES: OC([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)NC=1)(C(O)=O)CC(=NO)C(O)=O.Cl.C(=O)([O-])[O-].[Na+].[Na+].O[C@](CC1C2C(=CC=CC=2)NC=1)(C(O)=O)CC(=[N:37]O)C(O)=O>O.C(OCC)(=O)C>[C:22]1([C@H:14]([NH2:37])[CH3:13])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)C(CC(O)(Cc1c[nH]c2ccccc12)C(=O)O)=NO
Reactant: O=C(O)C(C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)=NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After 44.7 g (0.131 mol) of the ammonium salt of 4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid was dissolved in 500 ml of water at 25° C., the resulting aqueous solution was adjusted to pH 2 using 25.5 g of 36% hydrochloric acid. The acidic solution was extracted in 1300 ml of ethyl acetate, and the resulting ethyl acetate solution was rinsed with 200 ml of aqueous saturated sodium chloride solution. 500 ml of an aqueous sodium carbonate solution (13.9 g (0.131 mole) of sodium carbonate) was added to the resulting ethyl acetate solution for agitation, to separate the aqueous alkali solution from ethyl acetate. 23.1 g of 36% hydrochloric acid was added to the resulting aqueous alkali solution, to adjust the solution to pH 2. 6.99 g (57.6 mmol) of(R)-(+)-1-phenylethylamine was added dropwise to the resulting aqueous acidic solution and the solution stirred at 25° C. for one hour. The resulting crystal was filtered and dried under reduced pressure, to obtain 21.8 g (47.8 mmol) of the (R)-(+)-1-phenylethylamine salt of (4S)-4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid. (Yield, 72.7%; optical purity, 87.4%.)
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: Brc1cnc(Br)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cc2Br)CC1
Yield: 97.5 %

Procedure:
To a mixture of 2,3,5-tribromopyridine (10 g), 1-Boc-piperazine (6 g) and potassium carbonate (20 g) was added 2-butanone (80 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(3,5-dibromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (13 g). To a mixture of 4-(3,5-dibromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (13 g), bis(tricyclohexylphosphine)palladium (II) dichloride (1.3 g), tripotassium phosphate (38 g) and cyclopropylboronic acid (8.4 g) were added toluene (100 mL) and water (5 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (7 g). 4-(3,5-Dicyclopropylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (7 g) was dissolved in chloroform (25 mL), 4N hydrogen chloride/ethyl acetate (25 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution (100 mL), and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was dissolved in ethyl acetate (50 mL), 4N hydrogen chloride/ethyl acetate (8 mL) was added, and the mixture was filtered to give the title compound (3.2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C=O)C.O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2cc(O)ccc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2cc(OCCN3CCOCC3)ccc21
Temperature: 80 °C
Yield: 68.1 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-5-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one (60 mg, 0.18 mmol) obtained in Step 5 in DMF (2 mL) was added K2CO3(75 mg, 0.54 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (50 mg, 0.27 mmol). The mixture was heated to 80° C. for 3 h and cooled to room temperature. The resulting solution was diluted with H2O and extracted with EtOAc (5 mL×3). The extracts were washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (2% MeOH/CH2Cl2) to afford the title compound (55 mg, 68%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:11](Cl)([Cl:13])=[O:12]>>[N+:1]([C:4]1[CH:5]=[C:6]([O:10][C:11]([Cl:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: O=C(Cl)Cl
Product: O=C(Cl)Oc1cccc([N+](=O)[O-])c1

Procedure:
The 3-nitrophenyloxycarbonyl compound can be prepared by reaction of 3-nitrophenol with phosgene to yield 3-nitrophenyloxycarbonyl chloride. The latter can then be reacted with a thiol:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(-c2ccsc2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc(-c2ccsc2)c1
Yield: 61.4 %

Procedure:
A stirred solution of 9.8 g (0.056 mol) of 3-(3-methylphenyl)thiophene in 250 mL of carbon tetrachloride was heated to reflux, and 0.5 g of benzoyl peroxide was added. Heating was continued, and after five minutes an additional 0.5 g of benzoyl peroxide and 10 g of N-bromosuccinimide were added. Upon complete addition, the reaction mixture was heated under reflux for an additional 2.5 hours, then cooled in an ice-water bath for one hour. The reaction mixture was filtered, and the filter cake washed with 50 mL of carbon tetrachloride. The wash and filtrate were combined, and the whole was washed with 200 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residual oil. The residual oil was subjected to distillation under reduced pressure using a Kugelrohr distilling system to give 8.7 g of 3-(3-bromomethylphenyl)thiophene, b.p. 95°-150° C./0.1 mm.
Reaction SMILES: [CH2:1]([N:5]([CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]2[S:20][C:19]([CH:21]=O)=[CH:18][CH:17]=2)=[C:8]([O:23][CH3:24])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:29]([C:31]1[C:32](=[C:47]([C:50]#[N:51])[C:48]#[N:49])[O:33][C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:37]([F:40])([F:39])[F:38])[C:35]=1[CH3:36])#[N:30]>C(O)C>[CH2:25]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]2[S:20][C:19]([CH:21]=[CH:36][C:35]3[C:34]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:37]([F:40])([F:38])[F:39])[O:33][C:32](=[C:47]([C:50]#[N:51])[C:48]#[N:49])[C:31]=3[C:29]#[N:30])=[CH:18][CH:17]=2)=[C:8]([O:23][CH3:24])[CH:7]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=CC=Cc2ccc(C=O)s2)c(OC)c1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)s2)c(OC)c1
Temperature: 50 °C
Yield: 78.5 %

Procedure:
In 8 ml of ethanol were dissolved 220 mg (0.55 mmol) of 5-[4-(4-dibutylamino-2-methoxyphenyl)-1,3-butadienyl]thiophene-2-carboaldehyde and 192 mg (0.61 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred with heating at 50° C. for 2.5 hours, the product was separated by filtration and washed with ethanol. The product was purified by silica gel column chromatography to give 300 mg of a black crystal (yield: 78.1%; mp: 125-140° C.)
Reaction SMILES: C[OH:2].[Cl:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1>N1C=CC=CC=1.O=O>[Cl:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:2])[C:6]=2[CH:5]=1
Reactant: CO
Reactant: Clc1ccc2c(c1)Cc1ccccc1-2
Agent: O=O
Solvent: c1ccncc1
Product: O=C1c2ccccc2-c2ccc(Cl)cc21

Procedure:
A methanol free, 40% solution of Triton B in pyridine (8 mL) was added to a stirred, room temperature solution of commercially available (Alpha) 2-chlorofluorene (17) (42 g, 0.21 mmoL) in pyridine (257 mL) and oxygen was bubbled through the mixture at a moderate rate for 18 h. The majority of the pyridine was then removed on the rotary evaporator at reduced pressure and 5% aqueous hydrochloric acid (500 mL) was added to the residue. The solid was collected by filtration and washed with 5% aqueous hydrochloric acid and water. After drying, the solid was extracted repeatedly with hexane to remove some hexane insoluble impurities. Evaporation of the hexane left 42.7 g(95%) of 2-chloro-9-fluorenone: mp 110°-113° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][O:25][CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[CH3:24][O:25][CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:22][C:16]1([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:15][CH:14]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: COC[C@@H]1CCCN1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCO
Product: COC[C@@H]1CCCN1CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 71.8 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (350 mg, 1.103 mmol), (s)-(+)-2-(methoxymethyl)pyrrolidine (230 mg, 2.00 mmol), absolute ethanol (40 ml), activated 3 Å molecular sieves (350 mg), titanium (IV) isopropoxide (1.62 ml, 5.48 mmol) and STAB (2.09, 9.74 mmol) were reacted in accordance with the general procedure D. The isolated crude product was purified by column chromatography on silica eluting with DCM:MeOH:NH3 (98:1:1) to give the title compound as a white solid (330 mg, 72%). 1H NMR (400 MHz, CDCl3) δ7.18 (d, 2H), 6.86 (d, 2H), 4.02 (t, 2H), 3.84-3.70 (m, 2H), 3.59 (td, 1H), 3.45 (td, 1H), 3.27 (s, 3H), 3.10 (dd, 1H), 3.02 (dd, 1H), 2.94 (d, 1H), 2.63 (t, 2H), 2.59-2.45 (m, 5H), 2.39 (m, 1H), 2.21 (m, 1H), 2.06-1.34 (m, 15H).
Reaction SMILES: [CH:1]1C2NC3C(=CC=CC=3)SC=2C=[CH:3][C:2]=1[C:15](N[C@H](C(N[C@H](C(N[C@H](C(N[C@H]1CCOC1O)=O)CC(C)C)=O)CC(C)C)=O)CC(C)C)=O.[CH:48]1[C:61]2[NH:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[S:53][C:52]=2[CH:51]=[CH:50][C:49]=1[O:62][CH2:63][C:64]([NH:66][C@H:67]([C:72]([NH:74][C@H:75]([C:80]([NH:82][C@H:83]1[CH2:87][CH2:86][O:85][CH:84]1[O:88][CH3:89])=[O:81])CC(C)C)=[O:73])CC(C)C)=[O:65]>>[CH:48]1[C:61]2[NH:60][C:59]3[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=3)[S:53][C:52]=2[CH:51]=[CH:50][C:49]=1[O:62][CH2:63][C:64]([NH:66][CH2:67][C:72]([N:74]([CH2:1][CH:2]([CH3:15])[CH3:3])[CH2:75][C:80]([NH:82][C@H:83]1[CH2:87][CH2:86][O:85][CH:84]1[O:88][CH3:89])=[O:81])=[O:73])=[O:65]
Reactant: COC1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)COc1ccc2c(c1)Nc1ccccc1S2
Reactant: CC(C)C[C@H](NC(=O)c1ccc2c(c1)Nc1ccccc1S2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CCOC1O
Product: COC1OCC[C@@H]1NC(=O)CN(CC(C)C)C(=O)CNC(=O)COc1ccc2c(c1)Nc1ccccc1S2

Procedure:
The compounds of Examples 40 to 58 were prepared according to the experimental protocol described for the compound of Example 2 starting from the compounds of Examples 21 to 39 respectively.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:13]3[N:14]=[C:15]([NH2:17])[S:16][C:12]=3[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=O.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C(OCC)(=O)C.C1COCC1>[CH3:29][O:28][C:26](=[O:27])[C:25]1[CH:30]=[CH:31][C:22]([CH2:20][NH:17][C:15]2[S:16][C:12]3[CH:11]=[C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:19]=[CH:18][C:13]=3[N:14]=2)=[CH:23][CH:24]=1
Reactant: Nc1nc2ccc(OCCN3CCOCC3)cc2s1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CNc2nc3ccc(OCCN4CCOCC4)cc3s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
To a round-bottom flask containing benzothiazole 226 (5.80 g, 20.8 mmol) was added methyl 4-formylbenzoate (5.11 g, 31.1 mmol), followed by THF (8 mL), dibutyltin dichloride (315 mg, 1.04 mmol) and dropwise addition of phenylsilane (3.24 mL, 31.1 mmol). The resulting mixture was stirred overnight at room temperature under nitrogen. The mixture was diluted in ethyl acetate and filtered. The filtrate was partitioned between ethyl acetate and water and the combined organic layers were washed with 1N HCl. The combined acidic layers were neutralized using a saturated aqueous solution of NaHCO3 and the precipitate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The resulting crude was purified by flash chromatography using MeOH/CHCl3 (10:90) to afford 227 (3.69 g, 42% yield). 1H NMR: (Acetone-d6) δ (ppm): 8.04 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 1H), 7.34 (d, J=2.5 Hz, 1H), 6.94 (dd, J=8.5, 2.7 Hz, 1H), 4.50 (t, J=5.5 Hz, 2H), 3.86 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[C:3]=1[CH3:14].[CH3:15][NH2:16].O>C(#N)C>[Cl:13][C:4]1[C:3]([CH3:14])=[C:2]([NH:16][CH3:15])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(Cl)c(C)c1Cl
Reactant: CN
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cnc(Cl)c(C)c1NC
Temperature: 50 °C
Reaction time: 72 h
Yield: 81 %

Procedure:
To a solution of ethyl 4,6-dichloro-5-methylnicotinate (2.6 g, 11.1 mmol) in acetonitrile (60 mL) was added dropwise 40% methylamine in water (689 mg, 22.2 mmol, 60 mL), and the mixture was stirred at 50° C. for 72 h. LCMS monitored the reaction was completed. The reaction mixture was concentrated and extracted with ethyl acetate (100 mL). The organic layer was separated, combined, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate=2:1) to get the title compound (2.05 g, 81%) as a colorless oil. MS (ES+) C10H13ClN2O2 requires: 228, 230. found: 229, 231 [M+H]+.