Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]2[C:18](=[O:23])[CH:19]([F:22])[CH:20]([F:21])[C:15]2=[N:14]1.[CH3:24][Mg]Br.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]2[C:18]([CH3:24])([OH:23])[CH:19]([F:22])[CH:20]([F:21])[C:15]2=[N:14]1
Reactant: C[Mg]Br
Reactant: O=C1c2cn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)nc2C(F)C1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(O)c2cn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)nc2C(F)C1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (87) (6.6 mg, 17.8 mmol) in 500 mL THF was added methyl magnesium bromide (10 mL, 3.0 M). The mixture was stirred at room temperature for 3 h. The mixture was poured into 5 mL dilute NaHCO3 solution. The aqueous solution was extracted with dichloromethane (5 mL×3). The organic layers were combined, washed with brine and dried with anhydrous sodium sulfate. The mixture was then chromatographed on a silica gel TLC plate using dichloromethane/ethyl acetate (9:1) to give (88): yield (32%): 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 2H), 7.57 (s, 1H), 5.89 (dd, 1H, J=4.25, 56.66 Hz), 4.92 (ddd, 1H, J=4.25, 15.76, 48.17 Hz), 2.47 (br s, 1H), 1.75 (s, 3H).
Reaction SMILES: C(OCCCCC#N)(=S)C.C[O-].[Na+].CS(O[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[C:37]2[C:32](=[CH:33][C:34]([O:38][CH3:39])=[CH:35][CH:36]=2)[S:31][CH2:30][C:29]1([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[CH3:40])(=O)=O.[C:49]([CH2:51][CH2:52][CH2:53][CH2:54][SH:55])#[N:50]>CO.O1CCCC1.O>[C:49]([CH2:51][CH2:52][CH2:53][CH2:54][S:55][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[C:37]2[C:36](=[CH:35][C:34]([O:38][CH3:39])=[CH:33][CH:32]=2)[S:31][CH2:30][C:29]1([C:41]1[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=1)[CH3:40])#[N:50]
Reactant: N#CCCCCS
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCOS(C)(=O)=O)cc1
Agent: CC(=S)OCCCCC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCSCCCCC#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-cyanobutyl thioacetate (613 mg, 3.90 mmol) in methanol (10 ml) and was added 1M sodium methoxide (3.06 ml) and stirred at room temperature for 1 h. Then (3RS,4RS)-4-(9-methansulfonyloxynonyl)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (290 mg, 0.557 mmol) dissolved in dry tetrahydrofuran (5 ml) was added dropwise thereto at room temperature and stirred overnight. When the reaction was completed, water was added to the reaction solution which was then extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure and flash chromatographed on silica gel (n-hexane:ethyl acetate=8:2) to give 495 mg (165%, contains the 4-cyanobutan-1-thiol) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([Sn](CCCC)(CCCC)CCCC)#[CH:2].Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][C:25]([CH3:28])=[N:26][N:27]=2)=[C:19]([O:29][CH3:30])[CH:18]=1>C1COCC1.[Cl-].[Na+].O.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:1]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][C:25]([CH3:28])=[N:26][N:27]=2)=[C:19]([O:29][CH3:30])[CH:18]=1)#[CH:2]
Reactant: COc1cc(Br)ccc1-c1nnc(C)o1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(-c2nnc(C)o2)c(OC)c1
Temperature: 120 °C
Yield: 50 %

Procedure:
Pd(Ph3P)4 (100 mg, 0.087 mmol) and ethynyltributylstannane (600 mg, 1.904 mmol) was treated with a solution of 2-(4-bromo-2-methoxyphenyl)-5-methyl-1,3,4-oxadiazole (457.7 mg, 1.701 mmol) in 10 ml of THF and heated to 120° C. for 15 minutes in a microwave. The reaction was dissolved in brine and extracted three times with EtOAc. Organics were combined, dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel (100% hexanes followed by 0-25% EtOAc/DCM) gave a cream-colored solid (180 mg, 0.850 mmol, 49%).
Reaction SMILES: Cl[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[C:4](=[O:15])[CH:3]=1>O1CCCC1>[OH:15][C:4]1[C:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=3)[C:4](=[O:15])[C:3]=2[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:13])[CH2:9]2
Reactant: COc1ccc2c(c1)C(=O)C(Cl)=CC2=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)c1c(cc3c(c1O)CCC(=O)C3)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the keten acetal VII (2.5 g; 8.9 mmol) in tetrahydrofuran (THF) (3 ml) is added dropwise at 0° C. to a solution of 3-chloro-6-methoxy-1,4-naphthoquinone (1.9 g; 8.6 mmol) in THF (20 ml). The reaction medium is stirred overnight at ambient temperature. After evaporation of the solvent, the solid obtained is added slowly to a solution of HF (25 ml)-SbF5 (5 ml) at -40° C. in a Teflon flask. The mixture is kept at -40° C. for 20 minutes and then poured slowly into 500 ml of a water/ice mixture. After extraction with methylene chloride, the organic phase is washed with water, dried over sodium sulfate and then evaporated. The tetracyclic ketone is purified by chromatography under pressure (eluent: CH2Cl2) (1.11 g; 40%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:14]=[C:13]([O:15]C)[C:12]([CH2:17][O:18][C:19]2[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=2[CH3:28])=[C:11]([CH3:29])[N:10]=1.Cl>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:14]=[C:13]([OH:15])[C:12]([CH2:17][O:18][C:19]2[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[CH:21][C:20]=2[CH3:28])=[C:11]([CH3:29])[N:10]=1
Reactant: COc1nc(-c2c(C)cccc2C)nc(C)c1COc1cc(C(C)C)ccc1C
Agent: Cl
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(-c2c(C)cccc2C)nc1O
Temperature: 100 °C

Procedure:
A mixture of 2-(2,6-dimethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-4-methoxy-6-methylpyrimidine (1.29 g, 3.30 mmol) and 6 N HCl is heated at 100° C. for 3 h (until starting material is consumed as determined by LC/MS analysis). The resulting mixture is adjusted to pH 6 using 10 N NaOH and extracted with EtOAc (100 mL×3). The combined extracts are washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain a yellow gum. Purification by chromatography on silica gel (50-100% EtOAc/Hexanes) provides the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 11.4 (br, s, 1H), 6.75-7.26 (m, 6H), 5.00 (s, 2H), 2.86 (m, 1H), 2.51 (s, 3H), 2.22 (s, 6H), 2.19 (s, 3H), 1.24 (d, J=6.8 Hz, 6H); LC-MS found 377.4 (MH+), rt=2.87 min, Method 3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)/[CH:5]=[CH:6]/[C:7]([O:9]CC)=O.[CH2:15]([NH2:17])[CH3:16].C[O-].[Na+].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH:5]=[CH:6][C:7]([NH:17][CH2:15][CH3:16])=[O:9]
Reactant: CCN
Reactant: CCOC(=O)/C=C/c1cccc(Br)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCNC(=O)C=Cc1cccc(Br)c1
Temperature: 45 °C

Procedure:
Trans ethyl 3-bromocinnamate (8.4 g), ethylamine (6.7 g), methanol (18 ml) and 4A molecular sieves (1 g) were combined and heated at reflux for 1/2 hour. The mixture was cooled to about 45° C. and sodium methylate (0.6 g) added. The mixture was then heated at reflux 11/2 hour and then cooled. It was acidified with concentrated hydrochloric acid (12 ml). The sieves were removed by filtration. Ice water was added to the filtrate to precipitate trans 3-bromo-N-ethylcinnamamide, m.p. 89°-90° C. (after recrystallization from ethanol/water).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]Br.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH2:12][Br:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: CC(=O)CC(=O)NCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CBr)CC(=O)NCc1ccccc1
Temperature: 22.5 °C
Yield: 80.9 %

Procedure:
To a solution of N-benzyl-3-oxobutanamide (compound A 100 g, 522.9 mmol) in dichloromethane (500 ml) at 0-5° C. was added dropwise a solution of bromine (25.55 ml, 575.2 mmol) over 6 h. The reaction mixture was warmed up to 20-25° C. and stirred for 2 hours (bromine colour disappeared). An aqueous solution (600 mL) of sodium bicarbonate (65.9 g, 784.44 mmol) was added to the mixture. The organic layer was separated, washed with brine (200 mL), and then evaporated to dryness to give N-benzyl-4-bromo-3-oxobutanamide (114.25 g, quantitative) and was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=1[CH3:12].C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=1[CH2:12][Br:21]
Reactant: COC(=O)c1ccc(C#N)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C#N)cc1CBr
Temperature: 25 °C
Yield: 100.4 %

Procedure:
A mixture of 4-cyano-2-methyl-benzoic acid methyl ester (12.5 g, 71.35 mmol), NBS (12.7 g, 71.35 mmol) and di-benzoyl peroxide (BPO) (0.8 g, 3.28 mmol) in CCl4 (200 mL) was heated to reflux temperature for 3 hours. After it was cooled to room temperature, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give a crude product (18.2 g) which was used in the next step reaction without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[N:7][O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[Cl:21][C:22]1[C:27]([CH2:28][OH:29])=[CH:26][C:25]([F:30])=[C:24](Cl)[N:23]=1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CS(C)=O>[CH:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][N:7]=[C:4]2[CH2:3][CH2:2][N:1]([C:24]3[C:25]([F:30])=[CH:26][C:27]([CH2:28][OH:29])=[C:22]([Cl:21])[N:23]=3)[CH2:6][CH2:5]2)[CH2:14][CH2:13]1)=[O:16])([CH3:20])[CH3:19]
Reactant: OCc1cc(F)c(Cl)nc1Cl
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3nc(Cl)c(CO)cc3F)CC2)CC1
Temperature: 130 °C
Yield: 29.2 %

Procedure:
2d (0.48 g, 1.7 mmol), 55a (0.36 g, 1.86 mmol) and diisopropylethylamine (0.31 mL, 1.9 mmol) were combined in 5 mL of DMSO and heated at 130° C. for 2 days. The mixture was cooled, poured into ethyl acetate (15 mL), washed with water (10 mL) and brine (10 mL), dried and concentrated. The residue was purified by flash chromatography (eluent: 10 to 50% ethyl acetate+0.1% triethylamine in hexane) to afford 55b as a yellow oil (0.22 g, 30% yield): LC-MS 425.1 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1(=[O:37])[NH:35][C:34](=[O:36])[CH:33]=[CH:32]1>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[NH:14][C:13]3[CH:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH2:28][O:29][CH3:30])[C:33]4[C:34](=[O:36])[NH:35][C:31](=[O:37])[C:32]=4[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOc1ccccc1/C=C/c1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: O=C1C=CC(=O)N1
Product: COCCOc1ccccc1-c1cc2[nH]c3ccc(OCc4ccccc4)cc3c2c2c1C(=O)NC2=O
Yield: 46 %

Procedure:
Reaction of (852) with maleimide using the procedure described in method 4a gave the adduct (CIII; Ar=2-(2-methoxyethoxy)phenyl, R10═H (853), which was used without further purification. Aromatisation of (853) with MnO2 using the procedure described in example 79 gave (854) (46%) as an orange solid, mp 157–159° C., which was used without further purification.
Reaction SMILES: [B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[F:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:32][CH2:31][CH2:30][C@@H:29]2[C:33]2[CH:34]=[C:35]([C:50](O)=[O:51])[CH:36]=[C:37]3[C:42]=2[O:41][C:40]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[CH:39][C:38]3=[O:49])[CH:25]=[CH:26][CH:27]=1.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:32][CH2:31][CH2:30][C@@H:29]2[C:33]2[CH:34]=[C:35]([C:50]([N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)=[O:51])[CH:36]=[C:37]3[C:42]=2[O:41][C:40]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[CH:39][C:38]3=[O:49])[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1cc([C@H]2CCCN2c2cccc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: C1COCCN1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cc([C@H]2CCCN2c2cccc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.6 %

Procedure:
TSTU (220 mg, 0.68 mmol) was added in one portion to a stirred suspension of 8-[(2R)-(1-(3-fluorophenyl)pyrrolidin-2-yl)]-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (250 mg, 0.57 mmol, >98% enantiomeric purity, see Example 1.06 for details of preparation), morpholine (0.075 mL, 0.86 mmol) and DIPEA (0.149 mL, 0.86 mmol) dissolved in DCM (5 mL) at room temperature under nitrogen. The resulting suspension was stirred at room temperature for 16 h. The reaction mixture was purified by preparative HPLC. The fractions were evaporated to dryness, the obtained foam was dissolved in DCM (0.5 mL) and diethyl ether (1 mL) was added. The resulting crystalline solid was collected by filtration and dried under vacuum to give 8-[(2R)-(1-(3-fluorophenyl)pyrrolidin-2-yl)]-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-one (126 mg, 44%) as a white crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.F[C:8]1[CH:18]=[CH:17][C:11]([C:12](OCC)=[O:13])=[CH:10][CH:9]=1>>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:8]2[CH:18]=[CH:17][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=2)[CH:6]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Cc1c[nH]cn1
Product: Cc1cn(-c2ccc(CO)cc2)cn1

Procedure:
Prepared from 4-methylimidazole and ethyl 4-fluorobenzoate.
Reaction SMILES: [I:1]I.[Si:3]([O:10][CH2:11][CH:12]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)[CH2:13]O)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:6]([Si:3]([O:10][CH2:11][CH:12]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)[CH2:13][I:1])([CH3:5])[CH3:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: II
Reactant: CC(C)(C)[Si](C)(C)OCC(CO)COc1ccc(OC(F)(F)F)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(CI)COc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.3 %

Procedure:
A solution of iodine (2.89 g, 11.4 mmol) in anhydrous CH2Cl2 (6×10 mL, then 5mL+2 mL to rinse) was added dropwise (over 100 min) to a stirred mixture of alcohol 168 (3.28 g, 8.62 mmol), imidazole (1.50 g, 22.0 mmol) and triphenylphosphine (2.83 g, 10.8 mmol) in anhydrous CH2Cl2 (20 mL) under N2. After stirring at room temperature for 15 h, the resulting mixture was concentrated under reduced pressure, and the residue was chromatographed on silica gel. Elution with petroleum ether firstly gave foreruns, and then further elution with 5-20% CH2Cl2/petroleum ether gave tert-butyl(3-iodo-2-{[4-(trifluoromethoxy)phenoxy]methyl}propoxy)dimethylsilane (170) (3.90 g, 92%) as a pale brown oil; NMR (CDCl3) δ 7.13 (br dd, J=9.1, 0.7 Hz, 2H), 6.89 (dt, J=9.1, 3.0 Hz, 2H), 4.01 (dd, J=9.3, 5.7 Hz, 1H), 3.94 (dd, J=9.3, 6.2 Hz, 1H), 3.75 (dd, J=10.1, 5.6 Hz, 1H), 3.70 (dd, J=10.1, 5.6 Hz, 1H), 3.39 (dd, J=10.1, 5.9 Hz, 1H), 3.37 (dd, J=10.1, 6.0 Hz, 1H), 2.10 (sept, J=5.8 Hz, 1H), 0.89 (s, 9H), 0.07, 0.06 (2 s, 6H); HRCIMS calcd for C17H27F3IO3Si m/z [M+H]+ 491.0726. found 491.0721.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[C:6]1(=[O:11])[CH2:10][CH2:9][CH:8]=[CH:7]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[N:1]1[N:2]([CH:8]2[CH2:9][CH2:10][C:6](=[O:11])[CH2:7]2)[N:3]=[CH:4][CH:5]=1
Reactant: O=C1C=CCC1
Reactant: c1c[nH]nn1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1CCC(n2nccn2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1,2,3-triazole (3.5 g.), cyclopent-2-enone (5.0 g.), benzyltrimethylammonium hydroxide (40% w/v solution in MeOH; 2.0 ml.) and dioxan (20 ml.) was stirred at room temperature overnight. The mixture was evaporated, treated with EtOAc, washed twice with water and once with brine, dried (MgSO4), and evaporated to give unpurified 3-(1,2,3-triazol-2-yl)cyclopentanone as a pale yellow oil. The n.m.r. spectrum of the product exhibited the following resonances: 7.62 (s, 2H); 5.37 (br quintet, 1H); 3.1-1.8 (m, 6H). (solvent CDCl3)
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:20][SH:21].[Na]>CN(C)C=O>[CH3:20][S:21][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1F
Reactant: CS
Agent: [Na]
Solvent: CN(C)C=O
Product: CSc1cc(-c2ccc(C(F)(F)F)cc2)ccc1C#N
Temperature: 60 °C
Reaction time: 6 h
Yield: 75.4 %

Procedure:
To 3.0 g (11.3 mmol) of 2-fluoro-4-(4-trifluoromethylphenyl)benzonitrile in 50 ml of N,N-dimethylformamide, 7.0 g (15.0 mmol) of 15% aqueous sodium methyl mercaptan was added dropwise at room temperature. After 6 hours of stirring at 60° C., the reaction mixture was poured into 200 ml of ice-cold water and extracted with 100 ml of ethyl acetate twice. The ethyl acetate layer was washed with 100 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 2.5 g of 2-methylthio-4-(4-trifluoromethylphenyl)benzonitrile (yield 75%) as white crystals (m.p. 128-129° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[O:26]1[CH2:27][CH2:28][N:23]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][CH:11]=3)[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=2)[CH2:24][CH2:25]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)nc1NCc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A mixture of 6-chloro-N-(naphthalen-1-ylmethyl)-3-nitropyridin-2-amine (3.21 g, 10.2 mmol), morpholine (2.66 g, 30.6 mmol) and K2CO3 (2.11 g, 15.3 mmol) in DMF (50 mL) was stirred at 80° C. for 1 h. It was cooled to room temperature and poured into water (300 mL). It was extracted with EA (300 mL×2). The combined organic layers were washed with brine (300 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with EtOAc/Pet ether=1/1 to afford the desired product as a yellow solid (3.56 g, 96%); LC/MS: MS (ES+) m/e 365 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.53 (t, J=4.2 Hz, 4H), 3.60 (t, J=4.2 Hz, 4H), 5.19 (d, J=5.7 Hz, 2H), 6.33 (d, J=9.6 Hz, 1H), 7.44-7.61 (m, 4H), 7.85 (d, J=7.5 Hz, 1H), 7.97 (d, J=7.5 Hz, 1H), 8.12 (d, J=9.6 Hz, 1H), 8.21 (d, J=7.5 Hz, 1H), 9.25 (t, J=5.7 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH:13]=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:19]Br.N1(C2CCCCCCC2)CCCCCCN1>C(Cl)(Cl)(Cl)Cl.CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH:13]=[C:12]([Br:19])[C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: COC(=O)C1=CC(NC(=O)OC(C)(C)C)CC=C1
Agent: C1CCCC(N2CCCCCCN2)CCC1
Solvent: CC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C1=CC(NC(=O)OC(C)(C)C)CC=C1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2.53 g (10 m mole) of methyl 3-(tert-butoxycarbonylamino)-1,5-cyclohexadienecarboxylate in 40 ml of carbontetrachloride at 0° C. is treated dropwise with 1.60 g (10 m mole) of bromine. The solution is stirred at 25° C. for 12 hours, then evaporated under reduced pressure to afford the crude dibromide which is dissolved in 40 ml of acetone and treated with 1.2 g (10 m mole) of diazabicyclooctane for 12 hours at 25° C. The solvent is evaporated under reduced pressure, and the residue is treated with ether and water. The organic phase is dried and evaporated to afford methyl 3-tert-butoxycarbonylamino-6-bromo-1,5-cyclohexadienecarboxylate.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[C:16](=O)[C:15]2[C:14]([C:18]([O:20]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][CH:8]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.[NH2:30][NH2:31]>CO>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[C:16]2=[N:30][NH:31][C:18](=[O:20])[C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([C:15]=32)[NH:9][CH:8]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccccc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
A mixture of ethyl 3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (140 mg) in 85% hydrazine monohydrate (3 mL) and methanol (5 mL) was stirred at room temperature for 2 days. The resulting mixture was filtered and the residue was washed with water (20 mL) and methanol (5 mL) to obtain a white solid. The solid was dried in vacuum at 50° C. to obtain 9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (95 mg, yield 74%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.40 (s, 3H), 4.64-4.67 (d, J=10.8 Hz, 1H), 4.92-4.94 (d, J=10.4 Hz, 1H), 6.72 (s, 1H), 6.87 (s, 1H), 7.15-7.17 (d, J=8.4 Hz, 2H), 7.26-7.30 (m, 3H), 7.38 (s, 3H), 7.55-7.59 (t, J=7.6 Hz, 1H), 12.15 (s, 1H); LC-MS (ESI) m/z: 344 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:11][CH3:12])[C:6]=2[N:5]=[C:4]2[CH2:13][CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17](=O)[C:3]=12.O.[NH2:24][NH2:25]>C(O)C>[CH2:11]([N:10]1[N:9]=[CH:8][C:7]2[C:2]3[NH:25][N:24]=[C:17]4[C:16]5[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=5[CH2:14][CH2:13][C:4]([C:3]=34)=[N:5][C:6]1=2)[CH3:12]
Reactant: CCn1ncc2c(Cl)c3c(nc21)CCc1ccccc1C3=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCn1ncc2c3[nH]nc4c3c(nc21)CCc1ccccc1-4
Yield: 97 %

Procedure:
A mixture of 11.0 g. of 4-chloro-1-ethyl-10,11-dihydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin5(1H)one (0.035 mol.), 4.5 g. of hydrazine hydrate 98% (0.09 mol.) and 125 ml. of abs. ethanol is refluxed for 3 hours with stirring. Then the reaction solution is filtered while hot and allowed to crystallize in a refrigerator. The crystallized 2,5,7,8-tetrahydro-5-ethyl-1,2,4,5,6-pentaazabenzo[6,7]cyclohepta[1,2,3-cd]-as-indacene which is filtered off, washed with alcohol and ether, melts at 229°-231°. Evaporation of the mother liquor to dryness and treatment with water yields a further crop of 1.9 g. of the product. Total yield 97%. Recrystallization from ethanol elevates the melting point to 230°-232°.