Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C([N:21]([C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH:42]=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])CCCCCCCCCCCCCCCCC.[CH3:48][S:49]([C:52]1[CH:66]=[CH:65][C:55]([CH2:56]P(=O)(OCC)OCC)=[CH:54][CH:53]=1)(=[O:51])=[O:50]>COCCOC>[CH2:22]([N:21]([CH2:40][CH2:47][CH2:46][CH2:45][CH2:44][CH2:41][CH2:42][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])[C:46]1[CH:47]=[CH:40][C:41]([CH:42]=[CH:56][C:55]2[CH:54]=[CH:53][C:52]([S:49]([CH3:48])(=[O:50])=[O:51])=[CH:66][CH:65]=2)=[CH:44][CH:45]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCOP(=O)(Cc1ccc(S(C)(=O)=O)cc1)OCC
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)c1ccccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)c1ccc(C=Cc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 0 °C
Yield: 101.5 %

Procedure:
To a solution of 420 mG of 60% sodium hydride dispersion (0.011 mol), 6.26 g (0.01 mol) of N,N-dioctadecylaminobenzaldehyde and 40 mL of dry, freshly distilled 1,2-dimethoxyethane (DME) under nitrogen, at room temperature, with vigorous stirring, was added a solution of 3.06 g (0.01 mol) of diethyl 4-methylsulfonylbenzylphosphonate in 10 mL 1,2-dimethoxyethane. The mixture immediately turned bright yellow. The reaction mixture was heated at reflux for 2 hours. After cooling, the bright yellow solution was poured over 100 g of crushed ice under a nitrogen blanket. The bright yellow solid was collected by filtration, washed with cold water, and air dried. Recrystallization from ethanol yielded 3.95 g (50.7%) of bright yellow powder mp 75°-76° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([OH:14])(=[O:13])=[O:12].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH:15]1([NH:21][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[S:11]([OH:14])(=[O:13])=[O:12])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)O)c1
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(NC2CCCCC2)c(S(=O)(=O)O)c1

Procedure:
To 4-chloro-3-sulphonitrobenzene (130 g) in water (2 liters) was added cyclohexylamine (75 ml) and sodium carbonate (26.5 g). The reaction mixture was heated at 90° for 10 hours, cooled and the solid so formed isolated by filtration to give 4-cyclohexylamino-3-sulphonitrobenzene (120 g).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].O=[C:8]([CH3:22])[CH2:9][CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][C:13]1=[O:21]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:1][C:8](=[CH2:22])[CH2:9][CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][C:13]1=[O:21]
Reactant: CC(=O)CCCn1c(=O)oc2ccccc21
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)CCCn1c(=O)oc2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 61.1 %

Procedure:
Potassium tert-butoxide (3.5 g, 31.2 mmol) was gradually added to a mixture of methyltriphenylphosphonium bromide (11 g, 30.8 mmol) in THF (100 ml) while cooling in an ice-bath, and the mixture was stirred for 20 minutes. To which a solution of 3-(4-oxopentyl)-3H-benzoxazol-2-one (5.6 g, 25.6 mmol) in THF (10 ml) was gradually added dropwise. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate twice. The extract was washed with water and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to afford 3-(4-methyl-4-pentenyl)-3H-benzoxazol-2-one (3.4 g, yield 61%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]([C:7]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][C:8]=2[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:5][CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH3:30]O>>[CH3:1][C:2]1([CH3:24])[C:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:30])=[O:14])[CH:10]=[CH:9][C:8]=2[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCC=C1c1cc(C(=O)O)ccc1-c1cc(O)ccc1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(-c2cc(O)ccc2F)c(C2=CCCC2(C)C)c1
Yield: 98 %

Procedure:
To a flask containing 66.14A (75 mg, 230 μmol) in MeOH (2 mL) was added sulfuric acid (0.61 μL, 11 μmol), and the mixture was stirred at reflux overnight. The reaction was concentrated and then purified by silica gel chromatography (0 to 30% EtOAc/Hexanes) to provide 66.14B (77.0 mg, 98% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2].C(COC)OC.[CH3:23][NH:24][NH2:25]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2[N:10]=[N:11][C:12]([N:24]([CH3:23])[NH2:25])=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CNN
Reactant: CCOC(=O)N1CCc2nnc(Cl)cc2C1
Solvent: COCCOC
Product: CCOC(=O)N1CCc2nnc(N(C)N)cc2C1

Procedure:
72.6 g of 3-chloro-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester are heated at reflux in 300 cc of methylhydrazine at a bath temperature of 110° for 1 hour while stirring, and the mixture is concentrated, the residue divided between chloroform and water and after concentrating the chloroform phase the title compound is obtained, M.P. 121°-123° (dec., from dimethoxyethane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:22]1([CH:28]2[CH2:33][CH2:32][N:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>N1C=CC=CC=1>[N:22]1([CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:21][C:18]3[CH:17]=[CH:16][C:15](/[CH:14]=[C:11](\[C:12]#[N:13])/[C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[CH:20][CH:19]=3)=[O:35])[CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc(/C(C#N)=C/c2ccc(O)cc2)cc1OC
Reactant: O=C(Cl)N1CCC(N2CCCCC2)CC1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(/C(C#N)=C/c2ccc(OC(=O)N3CCC(N4CCCCC4)CC3)cc2)cc1OC
Yield: 80.3 %

Procedure:
(Z)-2-(3,4-dimethoxyphenyl)-3-(4-hydroxyphenyl)acrylonitrile (compound 1) (0.28 g) and 4-piperidinopiperidinocarbonyl chloride (0.23 g) were dissolved in pyridine (5 ml), and the resultant solution was stirred for a whole day and night. After completion of reaction, the resultant reaction mixture was added to water (200 ml), and the thus-precipitated product was purified by means of silica gel chromatography employing a chloroform/methanol system, to thereby produce the target product (0.38 g, yield: 79%).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10]([C:18]4[CH:23]=[C:22]([I:24])[C:21]([OH:25])=[C:20]([I:26])[CH:19]=4)=[C:11]4[C:16](=[CH:17][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4.[C:27]([O:32]C)(=[O:31])[C@H:28]([CH3:30])O>>[CH:1]1[C:9]2[C:8]3[C:10]([C:18]4[CH:19]=[C:20]([I:26])[C:21]([O:25][C@H:28]([CH3:30])[C:27]([OH:32])=[O:31])=[C:22]([I:24])[CH:23]=4)=[C:11]4[C:16](=[CH:17][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4
Reactant: COC(=O)[C@H](C)O
Reactant: Oc1c(I)cc(-c2c3ccccc3cc3sc4ccccc4c23)cc1I
Product: C[C@@H](Oc1c(I)cc(-c2c3ccccc3cc3sc4ccccc4c23)cc1I)C(=O)O

Procedure:
Prepared from of 4-(benzo[b]naphtho[2,3-d]thiophen-11-yl)-2,6-diiodo-phenol (Example 26) and commercially available (S)-lactic acid, methyl ester. White solid: mp 134-136: NMR (CDCl3): δ8.38 (s, 1 H), 7.95 (dd J=8, 6 Hz, 1 H), 7.93 (d, J=1 Hz, 2 H), 7.81 (d, J=8 Hz, 1 H), 7.58 (ddd, J=8, 7, 1 Hz, 1 H), 7.59-7.54 (m, 2 H), 7.49-7.40 (m, 2 H), 7.15(ddd, J=8, 7, 1 Hz, 1 H), 6.77 (d, J=8, 1 Hz, 1 H), 5.48 (q, J =7 Hz, 1 H), 1.82 (d, J=7 Hz, 2 H); MS (+FAB): [M+H]+, 651; Anal. Calc. for C26H16I2O3S: C, 46.18, H, 2.48, N, 0.00. Found: C, 46.60, H, 2.50, N, 0.21.
Reaction SMILES: [O-]CC.[Ca+2].[O-]CC.[CH2:8]1[O:12][CH:9]1[CH2:10][CH3:11].[I:13][C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:15]=1[OH:21].Cl>>[I:13][C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:15]=1[O:21][CH2:8][CH:9]([OH:12])[CH2:10][CH3:11]
Reactant: CCC1CO1
Reactant: Oc1ccc(I)cc1I
Agent: CC[O-]
Agent: Cl
Agent: [Ca+2]
Product: CCC(O)COc1ccc(I)cc1I
Temperature: 80 °C
Yield: 65.7 %

Procedure:
A suspension of calcium ethoxide (816 mg, 6.3 mmol), butene oxide (5.2 mL, 93 mmol) and 2,4-diiodophenol (2.17 g, 6.3 mmol) is heated in a sealed flask at 80° C. for 18 h. The reaction mixture is allowed to cool, poured into 1N HCl and extracted three times with CH2Cl2. The combined organic extracts are dried (Na2SO4), filtered and concentrated in vacuo. The resulting material is purified by column chromatography (two columns, step gradient of 30-40-50% CH2Cl2 in hexanes) to give 1-(2,4-diiodophenoxy)butan-2-ol as a clear oil (1.73 g, 67%).1H NMR (400 MHz, CDCl3) δ 8.04, 7.56, 6.57, 4.03, 3.9, 3.84, 2.42, 1.65, 1.04.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[N:7]([CH2:15][CH2:16][CH3:17])[C:5]1=[O:6])[CH2:2][CH3:3].Cl[CH2:19][P:20](=[O:23])([CH3:22])[CH3:21]>>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[N:11]([CH2:19][P:20](=[O:23])([CH3:22])[CH3:21])[CH:10]=[N:9][C:8]=2[N:7]([CH2:15][CH2:16][CH3:17])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: CP(C)(=O)CCl
Reactant: CCCn1c(=O)c2[nH]cnc2n(CCC)c1=O
Product: CCCn1c(=O)c2c(ncn2CP(C)(C)=O)n(CCC)c1=O

Procedure:
The title substance was prepared from 5 g (0.0186 mol) of 1,3-dipropyl-xanthine and 2.8 g (0.0224 mol) of chloromethyldimethylphosphine oxide analogously to Example 67.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[C:28]([C:27]([F:26])([F:35])[F:36])[CH:29]=1)=[O:7]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 83 %

Procedure:
To a solution of 3-bromo-4-methylbenzoic acid (1.0 equiv.) in DMF (1.2M) was added EDC (1.0 equiv.) and HOBt (1.0 equiv.) followed by 3-trifluoromethylaniline (1.0 equiv.) and the reaction was stirred at ambient temperature for 48 h. The reaction mixture was partitioned between ethyl acetate and water. The separated organic layer was dried with sodium sulfate and concentrated under vacuo. The concentrated crude was purified via silica gel chromatography and eluted with 0 to 100% ethyl acetate in heptanes to give 3-bromo-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide in 83% yield. LCMS (m/z) (M+H)=358/360, Rt=1.1 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Reactant: CCCNCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A mixture of 2-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.01845 mole) and 1,1'-carbonyldiimidazole (2.99 g, 0.01845 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for three hours with a stream of nitrogen bubbling through it. A solution of dipropylamine (5.6 g, 0.0554 mole) in tetrahydrofuran (7 ml) was added and the reaction mixture was refluxed overnight under nitrogen. The solvents were removed under reduced pressure and the residue was triturated in 100 ml of water, the solid was collected by filtration, rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot isopropyl alcohol, filtered hot, cooled to room temperature, and water was added to the cloud point. The resulting solid was collected by filtration, rinsed with water, and dried under high vacuum at 42° C. overnight to give 2.22 g (34%) of title compound, mp. 135°-136° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Pt](=O)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[NH:20][CH2:19][CH2:18][CH2:17]3)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Nc2cccc3cccnc23)cc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(Nc2cccc3c2NCCC3)cc1
Yield: 100.2 %

Procedure:
A solution of 2.46 grams of N-(4-tert-butylphenyl)quinolin-8-amine from Step A in 100 mL of acetic acid containing 0.15 grams of platinum(IV) oxide was hydrogenated at 45 psi for 1.5 hours on a Parr low-pressure hydrogenator. The solution was filtered through diatomaceous earth; concentrated in vacuo; and neutralized with 3N aqueous sodium hydroxide. The aqueous phase was diluted with water and extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with brine; dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield 2.5 grams of dark blue oil. The oil was chromatographed on silica gel, eluting with hexane/ethyl acetate (20:1) to afford 2.0 grams of the desired product as a yellow oil. 1H NMR (CDCl3) δ 7.2 (d, 2H), 6.5-6.95 (m, 5H), 4.95 (bs, 1H), 3.3 (t, 2H), 2.8 (t, 2H), 1.9 (p, 2H), 1.3 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:18][CH3:19])([CH2:16][CH3:17])[C:4]=2[CH:3]=1.[CH3:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[Sn](CCCC)(CCCC)CCCC>>[Br:15][C:8]1[CH:7]=[C:6]2[C:11]([C:12]3[CH:13]=[CH:14][C:2]([C:22]4[N:21]([CH3:20])[CH:25]=[CH:24][CH:23]=4)=[CH:3][C:4]=3[C:5]2([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:10][CH:9]=1
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Product: CCC1(CC)c2cc(Br)ccc2-c2ccc(-c3cccn3C)cc21

Procedure:
As shown in scheme 2, 2,7-dibromo-9,9-diethyl-9H-fluorene (21) is reacted with 1-methyl-2-(tributylstannyl)-1H-pyrrole by Stille coupling reaction to obtain 2-(7-bromo-9,9-diethyl-9H-fluoren-2-yl)-1-methyl-1H-pyrrole (22). Then, in the presence of sodium tert-butoxide, Pd(dba)2, and tri-tert-butyl phosphine, 2-(7-bromo-9,9-diethyl-9H-fluoren-2-yl)-1-methyl-1H-pyrrole (22) is reacted with diphenylamine to obtain 9,9-diethyl-7-(1-methyl-1H-pyrrol-2-yl)-N,N-diphenyl-9H-fluoren-2-amine (23a). n-butyl lithium is reacted with 9,9-diethyl-7-(1-methyl-1H-pyrrol-2-yl)-N,N-diphenyl-9H-fluoren-2-amine (23a), and then tributylstannylchloride is added thereto to obtain N-methyl-2-(7-diphenyl-amino-9,9-diethyl-9H-fluoren-2-yl)-5-tributylstannylpyrrole (24a). N-methyl-2-(7-diphenylamino-9,9-diethyl-9H-fluoren-2-yl)-5-tributyl-stannylpyrrole (24a) is reacted with 5-bromo-2-thiophene carboxaldehyde by Stille coupling reaction to obtain 5-[N-methyl-2-(7-diphenylamino-9,9-diethyl-9H-fluoren-2-yl)pyrrol-5-yl]thiophene-2-carbaldehyde (25a). Finally, 5-[N-methyl-2-(7-diphenylamino-9,9-diethyl-9H-fluoren-2-yl)pyrrol-5-yl]thiophene-2-carbaldehyde (25a) is reacted with cyanoacetic acid in acetic acid by using ammonium acetate as a catalyst, and (E)-2-cyano-3-[5-(N-methyl-2-(7-diphenylamino-9,9-diethyl-9H-fluoren-2-yl)pyrrol-5-yl)thiophen-2-yl]acrylic acid (26a) is obtained.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[CH:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[C:1]1([CH:7]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCc2cc(C(=Cn3ccnc3)c3ccccc3)ccc2N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1CCc2cc(C(Cn3ccnc3)c3ccccc3)ccc2N1

Procedure:
A solution of 390 mg of a mixture of (E) and (Z) isomers of 6-[1-phenyl-2-(imidazol-1-yl)ethenyl]-3,4-dihydrocarbostyril in 10 ml of ethanol was stirred under hydrogen in the presence of 200 mg of a 10% palladium on charcoal catalyst until the theoretical amount of hydrogen had been absorbed. The catalyst was filtered off, the solvent removed from the filtrate under reduced pressure and the residue chromatographed on silica gel eluting with 5% methanol in methylene chloride, yielding 6-[1-phenyl-2-(imidazol-1-yl)ethyl]-3,4-dihydrocarbostyril, having a melting point of 87°-94° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH:12]([CH3:15])[CH2:13][CH3:14])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[BH4-].[Na+]>CO>[NH2:2][C@@H:3]([CH:12]([CH3:15])[CH2:13][CH3:14])[C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: CCC(C)[C@H](N)C(=O)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(C)[C@H](N)[C@H](O)c1ccccc1
Temperature: 10 °C

Procedure:
The 2-(S)-amino-3-methyl-1-phenyl-1-pentanone hydrochloride (24.2 g, 0.106 mmol.) prepared above was dissolved in methanol (250 mL) The solution was stirred under chilling with ice to maintain the solution temperature at a temperature of lower than 10° C., and to this was portionwise added sodium borohydride (3.8 g, 0.10 mmol.) The reaction mixture was stirred for one hour at the same temperature, and concentrated under reduced pressure. To the residue were added chloroform (100 mL), water (50 mL), and 2N aqueous sodium hydroxide solution. The chloroform layer was separated, and the aqueous layer was subjected to extraction using chloroform The chloroform portions were combined, successively washed with water and aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, to give the titled compound as a white crystalline product (17.8 g, yield: 87%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:13]=[CH:14][C:15]3[C:21](=[O:22])[NH:20][C:19]4[CH:23]=[C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:25]=[CH:26][C:18]=4[NH:17][C:16]=3[CH:32]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].O[NH:34][C:35](=[NH:37])[CH3:36].CC(C)N=C=NC(C)C>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:13]=[CH:14][C:15]3[C:21](=[O:22])[NH:20][C:19]4[CH:23]=[C:24]([CH2:27][CH2:28][C:29]([O:31][NH:37][C:35](=[NH:34])[CH3:36])=[O:30])[CH:25]=[CH:26][C:18]=4[NH:17][C:16]=3[CH:32]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(=N)NO
Reactant: COc1cc(-c2ccc3c(c2)Nc2ccc(CCC(=O)O)cc2NC3=O)ccc1[N+](=O)[O-]
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(-c2ccc3c(c2)Nc2ccc(CCC(=O)ONC(C)=N)cc2NC3=O)ccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A mixture of Example 230 (65 mg, 0.15 mmol), N-hydroxy-acetamidine (14 mg, 0.18 mmol) in 1 mL of DMF was treated with DIC in 1 mL of CH2Cl2 at 0° C. The reaction mixture was stirred overnight and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 100:1 ethyl acetate/MeOH to provide the desired product. MS (DCI) m/e 490 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.01 (d, J=8.29 Hz, 1H), 7.94 (s, 1H), 7.79 (d, J=8.29 Hz, 1H), 7.52 (d, J=1.23 Hz, 1H), 7.33-7.34 (m, 2H), 7.29 (m, 1H), 6.93 (m, 1H), 6.83-6.85 (m, 2H), 6.27 (s, 2H), 4.03 (s, 3H), 2.73-2.76 (m, 2H), 2.58-2.62 (m, 2H), 1.72 (s, 3H).
Reaction SMILES: [OH:1][CH:2]([C:18]1[N:19](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:20]=[CH:21][N:22]=1)[CH:3]1[C:16](=[O:17])[N:7]2[C:8]3[C:13]([C:14]([CH3:15])=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3>C(O)(=O)C.O>[OH:1][CH:2]([C:18]1[NH:22][CH:21]=[CH:20][N:19]=1)[CH:3]1[C:16](=[O:17])[N:7]2[C:8]3[C:13]([C:14]([CH3:15])=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: Cc1c2n(c3ccccc13)C(=O)C(C(O)c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)CC2
Solvent: CC(=O)O
Solvent: O
Product: Cc1c2n(c3ccccc13)C(=O)C(C(O)c1ncc[nH]1)CC2
Yield: 71.7 %

Procedure:
A solution of 8,9-dihydro-7-[(hydroxy)(1-trityl-1H-imidazol-2-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (376 mg) in acetic acid (15 ml) and water (5 ml) was stirred at 60° C. for 2.5 hours. After evaporation of the solvent, the residue was diluted with water, neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted three times with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Purification of the residue with silica gel column chromatography (15% methanol-chloroform), followed by recrystallization from methanol, gave 8,9-dihydro-7-[(hydroxy)(1H-imidazol-2-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (148 mg).
Reaction SMILES: [CH2:1]([C:3]1([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]#[C:17][CH3:18])[CH3:2].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[CH2:1]([C:3]1([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3/[CH:16]=[CH:17]\[CH3:18])[CH3:2]
Reactant: [H][H]
Reactant: CC#Cc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: C/C=C\c1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
A mixture of 1-ethyl-8-(1-propynyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, methyl ester (155 mg, 0.5 mmol), Lindlar catalyst (15 mg), and methanol (10 mL) was charged with 1 atmosphere of hydrogen and allowed to stir at room temperature overnight. The catalyst was then removed by filtration through a celite plug, and the filtrate concentrated to give 170 mg of the crude product. This material was purified by flash chromatography (10% ethyl acetate/hexane, silica gel) to give the pure title compound as yellow oil (70 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[C:6]([CH:9]=1)[CH:7]=O.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[C:6]([CH:9]=1)[CH2:7][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: CC(C)COc1ccc(Br)cc1C=O
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)COc1ccc(Br)cc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-2-isobutoxybenzaldehyde (2.46 g) in 1,2-dichloroethane (40 ml) was added morpholine (0.96 ml) and acetic acid (0.57 ml). The mixture was stirred for 30 minutes before the addition of sodium triacetoxyborohydride (3.04 g). The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with saturated sodium bicarbonate (30 ml) and stirred for 30 minutes before extraction with ethyl acetate. The organic extracts were dried (MgSO4) and evaporated to give an oil, which was purified by column chromatography eluting with ethyl acetate/iso-hexane (20:80) to give 4-(5-bromo-2-isobutoxybenzyl)morpholine (2.88 g) as an oil.