Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)(=[O:3])[CH3:2]>C(O)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:8]=2[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cccc(Oc2ccccc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc2c(c1)oc1ccccc12
Yield: 15.7 %

Procedure:
A mixture of 3-phenoxybenzyl acetate 50 (21.8 g, 90 mmol) (prepared by acetylation of commercial 3-phenoxybenzyl alcohol) and palladium acetate (40 g, 179 mmol) in acetic acid (300 mL) was refluxed for 6 h, cooled and filtered. The filtrate was evaporated to dryness and the residue treated with 100 mL of a mixture cyclohexane/ethyl acetate (6/1) and filtered. The filtrate was concentrated to give a colored oil which was purified by chromatography on silica gel (cyclohexane/ethyl acetate, 6/1) to afford pure dibenzofuran-3-yl-methyl acetate 51 (3.4 g) and a mixture of dibenzofuran-3-yl-methyl acetate 51 (Rf=0.6) and dibenzofuran-1-yl-methyl acetate 52 contaminated with compound 51 (Rf of compound 52=0.53) (8.4 g) as a white solid.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][CH:21]1[CH2:24][N:23]([CH2:25][C@H:26]([OH:31])[C:27](OC)=[O:28])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[Si:13]([O:20][CH:21]1[CH2:24][N:23]([CH2:25][C@H:26]([OH:31])[C:27]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=2)=[O:28])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Cc1ccc(N)nc1
Reactant: COC(=O)[C@@H](O)CN1CC(O[Si](C)(C)C(C)(C)C)C1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)[C@@H](O)CN2CC(O[Si](C)(C)C(C)(C)C)C2)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
Trimethylaluminium (2M in toluene) (0.993 mL, 1.99 mmol) was added to 5-methylpyridin-2-amine (205 mg, 1.90 mmol) in toluene (10 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. (S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxypropanoate (Intermediate AD3) (500 mg, 1.73 mmol) in toluene (4 mL) was added and the reaction was allowed to warm to room temperature and then heated at 80° C. for 4 hours. The reaction mixture was concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water and extracted with EtOAc. The combined organics were dried (MgSO4) and evaporated to afford the product (482 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 0.05 (6H, s), 0.88 (9H, s), 2.30 (3H, s), 3.15-3.23 (1H, m), 3.37-3.51 (3H, m), 4.15-4.30 (2H, m), 4.32-4.39 (1H, m), 4.58-4.66 (1H, m), 7.48-7.53 (1H, m), 8.04 (1H, d), 8.12-8.15 (1H, m), 9.46 (1H, s); m/z (ES+) (M+H)+=366.53; HPLC tR=1.50 min.
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27]>>[OH:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:20][CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1C(=CO)C(c2ccccc2)Oc2ccccc21
Reactant: Nc1ccccc1O
Product: O=C1C(=CNc2ccccc2O)C(c2ccccc2)Oc2ccccc21

Procedure:
As in example 18 but starting from 5 g 3-hydroxymethylideneflavanone and 2.16 g o-aminophenol. Pure 3-(N-2-hydroxyphenyl)aminomethylidene-flavanone is obtained as yellow crystals; m.p. 226°-228° C.
Reaction SMILES: [C:1]([C:4]1[C:5]2[N:6]([N:10]=[C:11]([CH:23]3[CH2:25][CH2:24]3)[C:12]=2C(OCC2C=CC=CC=2)=O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[OH-].[K+].Cl>C(O)C.O>[C:1]([C:4]1[C:5]2[N:6]([N:10]=[C:11]([CH:23]3[CH2:25][CH2:24]3)[CH:12]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccn2nc(C3CC3)c(C(=O)OCc3ccccc3)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)c1cccn2nc(C3CC3)cc12
Reaction time: 3.5 h
Yield: 79.1 %

Procedure:
The compound of Example 40 (5.57 g) was dissolved in ethanol (30 mL) and water (30 mL). To this solution, potassium hydroxide (3.70 g) was added and the mixture was stirred for 3.5 hours under reflux. Subsequently, the mixture was neutralized with concentrated hydrochloric acid and extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the resulting solid product was dissolved in toluene (150 mL). This solution was stirred for 6 hours under reflux. Subsequent removal of the solvent and purification by silica gel column chromatography (hexane:ethyl acetate=4:1 then 1:1) afforded the title compound as a yellow powder (2.64 g) (Process D).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH:11]=[C:10]([SH:15])[CH2:9]1.Cl[CH2:17][C:18](=[O:20])[CH3:19].[O-]CC.[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH:11]=[C:10]([S:15][CH2:17][C:18](=[O:20])[CH3:19])[CH2:9]1
Reactant: CC(=O)CCl
Reactant: O=C1C=C(S)CC(c2ccccc2Cl)C1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)CSC1=CC(=O)CC(c2ccccc2Cl)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 103.5 %

Procedure:
To a solution of 5-(2-chlorophenyl)-3-mercapto-2-cyclohexen-1-one (1.8 g) and chloroacetone (0.7 g) in ethanol (20 ml) was added a solution of 20% sodium ethoxide in ethanol (0.48 g), and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and to the residue was ethyl acetate. The mixture was subjected to extraction, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give 5-(2-chlorophenyl)-3-(2-oxopropylthio)-2-cyclohexen-1-one (2.3 g).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][OH:12].Cl.C(N(C(C)C)CC)(C)C>C(O)C>[N:5]1[C:4]2[S:8][CH:9]=[CH:10][C:3]=2[C:2]([NH:11][OH:12])=[N:7][CH:6]=1
Reactant: Clc1ncnc2sccc12
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: ONc1ncnc2sccc12
Reaction time: 6 h

Procedure:
4-chlorothieno[2,3-d]pyrimidine (340 mg, 1.99 mmol), hydroxylamine-hydrogen chloride (550 mg, 7.91 mmol), and diisopropylethylamine (1 ml) in absolute ethanol (5 ml) was placed into a preheated oil bath at 75° C. After stirring for 6 h, the solution was concentrated under reduced pressure.
Reaction SMILES: ClCC1C=CC(C#N)=CC=1.Br[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1.[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([N:38]2[CH2:42][CH2:41][NH:40][C:39]2=[O:43])=[N:35][C:34]=1[CH3:44])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([CH2:13][CH2:12][N:40]2[CH2:41][CH2:42][N:38]([C:36]3[S:37][C:33]([C:31]([NH:30][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:32])=[C:34]([CH3:44])[N:35]=3)[C:39]2=[O:43])=[CH:15]1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Reactant: BrCCc1c[nH]c2ccccc12
Agent: N#Cc1ccc(CCl)cc1
Product: Cc1nc(N2CCN(CCc3c[nH]c4ccccc34)C2=O)sc1C(=O)NCc1ccccc1
Yield: 22 %

Procedure:
Following the procedure as described in Example 23, making variations as required to replace 4-(chloromethyl)benzonitrile with 3-(2-bromoethyl)-1H-indole to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 22% yield: mp 215-217° C. (dichloromethane/hexanes): 1H NMR (300 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.50 (t, J=6.0 Hz, 1H), 7.57 (d, J=6.0 Hz, 1H), 7.36-7.20 (m, 7H), 7.10-6.96 (m, 2H), 4.38 (d, J=6.0 Hz, 2H), 3.96 (t, J=9.0 Hz, 2H), 3.61-3.51 (m, 4H), 2.95 (t, J=9.0 Hz, 2H), 2.47 (s, 3H); MS (ES+) m/z 460.2 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH:3]([NH:8][C:9]([C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[N:15]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>C1COCC1>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:35])[NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[N:15]=[C:11]([C:9]([NH:8][CH:3]([CH:2]([CH3:25])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])=[O:10])[S:12][CH:13]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Reactant: O=C=Nc1ccccc1Cl
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccccc3Cl)cc2)cs1)C(C)C
Reaction time: 16 h

Procedure:
To methyl-2-(4-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 3, 170 mg) in THF (2 ml), 2-chlorophenyl isocyanate (94 mg) was added and reaction mixture was stirred for 16 hours. Organic solvent was concentrated obtained sticky solid, was purified by column chromatography (silica gel, EtOAc-petroleum ether) to obtain title compound as solid. Yield: 190 mg (76%). 1H NMR (DMSO-d6, 300 MHz): δ 9.58 (s, 1H), 8.80 (d, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 8.17 (d, 1H), 8.05 (d, 2H), 7.58 (d, 2H), 7.46 (d, 1H), 7.32 (t, 1H), 7.05 (t, 1H), 4.38 (t, 1H), 3.68 (s, 3H), 2.32 (m, 1H), 0.98 (t, 6H).
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:18]=1[CH2:19]Br>>[CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]2[CH2:19][C:18]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:17]=2[Cl:16])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ccc(Cl)c(CBr)c1
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Product: CC1(C)C(=O)N(C2CCCCCCC2)N1Cc1cc(Cl)ccc1Cl

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one and 2,5-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12](CCOC[Si](C)(C)C)[N:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[N:29][C:28]=23)=[O:23])[CH:5]=[CH:6][CH:7]=1.Cl>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[N:29][C:28]=23)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)COCCn1ncc(NC(=O)c2cnn3cccnc23)c1-c1cccc(Br)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(Nc1cn[nH]c1-c1cccc(Br)c1)c1cnn2cccnc12
Temperature: 70 °C
Reaction time: 6 h
Yield: 57.6 %

Procedure:
To a solution of N-(5-(3-bromophenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (742 mg, 1.45 mmol) in 20 mL of ethanol was added HCl (1.0 mL of a 6 M solution in water, 6 mmol). The reaction mixture was then stirred at 70° C. for 6 hours. After cooling to room temperature a light yellow precipitate formed, which was isolated by filtration and washed with methanol and diethyl ether. The filtrate was reduced in volume, and more solid product filtered. The combined collected solids were dried under vacuum to yield 320 mg (58%) of N-(5-(3-bromophenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=383.0; 1H NMR (400 MHz, DMSO-d6) δ13.01 (s, 1H), 9.93 (s, 1H), 9.33 (dd, 1H), 8.83 (dd, 1H), 8.66 (d, 1H), 8.26 (s, 1H), 7.57 (d, 1H), 7.47 (t, 1H), 7.28 (dd, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([N+:17]([O-])=O)[CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Br)ccc1NCCN1CCOCC1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1cc(Br)ccc1NCCN1CCOCC1
Yield: 96.9 %

Procedure:
Dissolve (4-bromo-2-nitro-phenyl)-(2-morpholin-4-yl-ethyl)-amine (15.3 g, 46.4 mmol) in ethyl acetate (1 L) and add 5% Pt/C (sulfided) (382 mg). Place the slurry under 60 psi hydrogen gas at room temperature of 8 h. Filter and concentrate to give 23 g crude product as a dark red oil. Purify using a short plug of silica gel and 10% 2N NH3 in MeOH/dichloromethane to give 13.5 g of a brown oil. HPLC (ISO60-10M) t=1.46 (94%), MS (ES) 301 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)[CH2:11][CH2:10]2)[NH:4][N:3]=1.CN(C)[CH:26]=[CH:27][C:28]([C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=O.[ClH:37]>C(O)(=O)C.C(O)(C)C>[ClH:37].[CH3:23][O:22][C:18]1[CH:17]=[C:16]([CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:5]3[C:6]([C:7]#[N:8])=[C:2]4[N:1]=[CH:26][CH:27]=[C:28]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[N:3]4[N:4]=3)[CH2:10][CH2:11]2)[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc(CN2CCN(c3[nH]nc(N)c3C#N)CC2)c1
Reactant: CN(C)C=CC(=O)c1cccnc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COc1cccc(CN2CCN(c3nn4c(-c5cccnc5)ccnc4c3C#N)CC2)c1

Procedure:
A mixture of 5.0 g of 3-amino-5-[4-[(3-methoxyphenyl)methyl]-1-piperazinyl]-1H-pyrazole-4-carbonitrile (prepared as described in Example 19) and 2.9 g of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (U.S. Pat. No. 4,281,000, Example 1) in 25 ml of glacial acetic acid was heated at reflux for 3 hours. The work procedure of Example 21 was followed to obtain a gummy solid. The solid was dissolved in isopropanol and was treated with 20 ml of 2.9N ethanolic hydrochloric acid. The yellow precipitate formed was collected by filtration, washed with isopropanol and dried in vacuo. The product was recrystallized from ethanol/water and gave 2.5 g of the desired product as a yellow solid, mp >250° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[CH:10]=1)[C:5]([OH:7])=[O:6].[Li]CCCC.[CH2:20]([O:22][P:23]([C:28]1[S:29][C:30]([CH:33]=[O:34])=[CH:31][CH:32]=1)(=[O:27])[O:24][CH2:25][CH3:26])[CH3:21]>C1COCC1>[CH2:20]([O:22][P:23]([C:28]1[S:29][C:30]([CH:33]([OH:34])[C:2]2[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[CH:10]=2)[C:5]([OH:7])=[O:6])=[CH:31][CH:32]=1)([O:24][CH2:25][CH3:26])=[O:27])[CH3:21]
Reactant: CCOP(=O)(OCC)c1ccc(C=O)s1
Reactant: CC(C)Oc1cc(Br)cc(C(=O)O)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1ccc(C(O)c2cc(OC(C)C)cc(C(=O)O)c2)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-5-isopropoxy-benzoic acid (2.0 g, 8.26 mmol) in THF (30 ml) was added 1.6 M nBuLi (10.6 ml, 16.94 mmol) at −78° C. The reaction was stirred at −78° C. for 1 h and treated with a solution of (5-formyl-thiophen-2-yl)-phosphonic acid diethyl ester (2.5 g, 9.91 mmol) in THF. After stirring at −78° C. for 30 min, the reaction mixture was warmed up to r.t. and quenched by water, diluted with EtOAc. The aqueous layer was separated, acidified with 2N HCl to pH<1, and extracted with EtOAc (3×). The combined EtOAc layers were dried over MgSO4, filtrated, concentrated to give the crude product 3-{[5-(diethoxy-phosphoryl)-thiophen-2-yl]-hydroxy-methyl}-5-isopropoxy-benzoic acid.
Reaction SMILES: ClC1C=C(C#N)C2C=C[N:8]([C:11]3[N:12]([CH2:22][CH3:23])[C:13](=[O:21])[NH:14][C:15](=[O:20])[C:16]=3[CH:17]([CH3:19])[CH3:18])C=2C=1.N1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[N:27]1>>[CH2:22]([N:12]1[C:11]([N:8]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[N:27]2)=[C:16]([CH:17]([CH3:18])[CH3:19])[C:15](=[O:20])[NH:14][C:13]1=[O:21])[CH3:23]
Reactant: c1ccc2[nH]ncc2c1
Reactant: CCn1c(-n2ccc3c(C#N)cc(Cl)cc32)c(C(C)C)c(=O)[nH]c1=O
Product: CCn1c(-n2ncc3ccccc32)c(C(C)C)c(=O)[nH]c1=O

Procedure:
This compound was made by a procedure similar to that used to prepare 6-chloro-1-(3-ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-1H-indole-4-carbonitrile (90), except that 1H-indazole was used instead of 6-chloro-1H-indole-4-carbonitrile. LC-MS shows 299.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 8.97 (br, 1H), 8.31 (s, 1H), 7.83 (d, 2H), 7.54 (m, 1H), 7.36 (m, 2H), 3.42 (m, 1H), 3.20 (m, 1H), 1.90 (m, 1H), 1.15 (dd, 6H), 1.00 (t, 3H).
Reaction SMILES: [CH:1](O)=[CH:2][CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C([Br:42])CCCCCCCCCCCCCCCCC>>[Br:42][CH2:22][CH2:21][CH2:20]/[CH:19]=[CH:18]\[CH2:17][CH:16]=[CH:15][CH2:14][CH:13]=[CH:12][CH2:11][CH:10]=[CH:9][CH2:8][CH:7]=[CH:6][CH2:5][CH:4]=[CH:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCC=CC=CC=CC=CC=CC=CO
Reactant: CCCCCCCCCCCCCCCCCCBr
Product: CCC=CCC=CCC=CCC=CCC=CC/C=C\CCCBr
Yield: 92 %

Procedure:
From docosahexaenyl alcohol 1e (201 mg, 0.64 mmol), using the procedure described above for preparation of 1-bromooctadecane (2a), (all-Z)-1-bromo-4,7,10,13,16,19-docosahexaene (2e) (221 mg, 92%) was obtained as a colourless oil.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5](Cl)[C:4]=1[C:19]([O:21][CH3:22])=[O:20].C(N(CC)CC)C.Cl.[NH2:32][CH2:33][C:34]#[N:35].Cl>CN(C=O)C>[F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH:35][CH2:34][C:33]#[N:32])[C:4]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1Cl
Reactant: N#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1NCC#N
Temperature: 25 °C

Procedure:
A solution of 3.0 g (0.008 mol) of product of Example 103, 1.72 g (0.017 mol) of triethylamine and 0.79 g (0.008 mol) of aminoacetonitrile hydrochloride in 30 ml of DMF was stirred at 50° C. for 24 hours. The reaction mixture was cooled to room temperature and poured into 3.7% HCl. This solution was extracted with diethyl ether. The ether phase was washed with H2O, and dried (MgSO4). The dry ether phase was concentrated in vacuo to 2.56 g of a brown semi-solid oil. The crude product was recrystallized in hexane/ethyl acetate to 0.9 g (28%) of product as a beige solid; mp 87°-89° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:15]1([N:21]2[C:33]3[CH:32]=[CH:31][C:30](B([O-])[O-])=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.COC(OC)(O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:15]1([N:21]2[C:33]3[CH:32]=[CH:31][C:30]([C:2]4[CH:3]=[CH:4][C:5]5[NH:6][C:7]6[C:12]([C:13]=5[CH:14]=4)=[CH:11][CH:10]=[CH:9][CH:8]=6)=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Reactant: [O-]B([O-])c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COC(C)(O)OC
Solvent: Cc1ccccc1
Product: c1ccc(-n2c3ccccc3c3cc(-c4ccc5[nH]c6ccccc6c5c4)ccc32)cc1
Yield: 80.8 %

Procedure:
Into a 200 mL three-neck flask were put 2.5 g (10 mmol) of 3-bromocarbazole, 2.9 g (10 mmol) of N-phenylcarbazole-3-boronate, and 152 mg (0.50 mmol) of tri(o-tolyl)phosphine. The air in the flask was replaced with nitrogen. To the mixture were added 50 mL of dimethoxyethanol (DME) and 10 mL of potassium carbonate solution (2 mol/L). Under reduced pressure, this mixture was degassed while being stirred. After the degassing, 50 mg (0.2 mmol) of palladium acetate was added to the mixture. This mixture was stirred at 80° C. for 3 hours under a stream of nitrogen. After the stirring, about 50 mL of toluene was added to this mixture. The mixture was stirred for about 30 minutes and then washed with water and a saturated aqueous sodium chloride solution in that order. After the washing, the organic layer was dried with magnesium sulfate. This mixture was subjected to gravity filtration. The obtained filtrate was condensed to give an oily substance. The obtained oily substance was dissolved in toluene. This solution was subjected to filtration through Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), alumina, and celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855). The obtained filtrate was condensed to give 3.3 g of a white solid, which was the object of the synthesis, in a yield of 80%. A synthesis scheme of Step 1 is shown in (b-1) given below.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[C:4]([CH3:11])[N:3]=1.S(Cl)(Cl)=O.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cc(C(=O)O)nc(Cl)n1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(CO)nc(Cl)n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
5.00 g (28.97 mmol) of 2-chloro-6-methylpyrimidine-4-carboxylic acid and 5.17 g (118.97 mmol) of thionyl chloride are initially charged in 60 ml of dry toluene and stirred at 60° C. for 3 h. The reaction solution is concentrated on a rotary evaporator, 20 ml of toluene are added to the residue and the mixture is again concentrated to dryness on a rotary evaporator. The residue is dissolved in 40 ml of methyl tert-butyl ether and cooled to 5° C. At this temperature, a solution of 2.41 g (63.74 mmol) of sodium borohydride in 40 ml of water is added. After warming to RT, the reaction mixture is kept at 4° C. for 24 h. 40 ml of ethyl acetate and 10 ml of sat. sodium bicarbonate solution are then added to the mixture. The organic phase is washed twice with in each case 10 ml of water. After drying of the organic phase over magnesium sulphate, the solvent is removed on a rotary evaporator.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][S:7]1(=[O:12])=[O:11].[CH2:19]([Li])CCC.IC.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][CH:8]([CH3:19])[S:7]1(=[O:12])=[O:11]
Reactant: [Li]CCCC
Reactant: COc1ccc(CN2CCCS2(=O)=O)c(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(CN2CCC(C)S2(=O)=O)c(OC)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution of 2-(2,4-dimethoxybenzyl)isothiazolidine-1,1-dioxide (0.600 g, 2.2 mmol) in anhydrous tetrahydrofuran (29 mL) was slowly added n-butyl lithium (1.725 mL of a 2.5 N solution in hexanes, 4.3 mmol). The reaction mixture was stirred for 1 hr at −78° C., iodomethane (0.688 mL, 11.1 mmol) was added, and the resulting mixture stirred for 2.5 hrs at −78° C. and 30 mins at room temperature. The mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (20-60% ethyl acetate/hexanes) to give the product as a clear oil (0.3 g). 1H NMR (CDCl3, 300 MHz) δ 7.25-7.22 (d, 1H, J=8.1 Hz), 6.48-6.43 (m, 2H), 4.27-4.13 (q, 2H, J=14.1 Hz), 3.80 (s, 3H), 3.79 (s, 3H), 3.25-3.02 (m, 3H), 2.43-2.32 (m, 1H), 1.95-1.83 (m, 1H), 1.42-1.40 (d, 3H, J=6.6 Hz).