Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:12][CH:11]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: OC(Cc1cnc(-c2c(F)cccc2F)nn1)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cccc(F)c1-c1ncc(C=Cc2ccc(Cl)cc2)nn1
Reaction time: 2 h

Procedure:
140 mg of 1-(4-chlorophenyl)-2-[3-(2,6-difluorophenyl)-[1,2,4]triazin-6-yl]-ethanol and 10 mg of p-toluenesulfonic acid in 10 ml of toluene are boiled under reflux using a water separator for 2 h; the reaction mixture is then poured into water, and the toluene phase is separated off, dried with sodium sulfate and concentrated by evaporation. After recrystallisation of the residue from cyclohexane, the title compound having a melting point of 135-140° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:14].[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CC(=O)OCC>[Cl:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])[CH:5]=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(S(F)(F)(F)(F)F)cc1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(S(F)(F)(F)(F)F)cc1Cl
Reaction time: 48 h
Yield: 93.1 %

Procedure:
5.50 g of 2-chloro-4-pentafluorosulfanylphenol, 7.89 g of K2CO3 and 4.05 g of CH3I were stirred at RT in 30 ml of anhydrous DMF for 2 hours and left to stand at RT for 2 days. The mixture was then diluted with 300 ml of EA and washed 3 times with 100 ml each time of water. Drying was effected with Na2SO4 and the solvent was removed under reduced pressure to obtain 5.40 g of a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].N1C=CC=CC=1.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[C:20]([O:8][C:7]1[C:2]([F:1])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9])(=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCOC(=O)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
In 50 ml of toluene, 16.5 g (90 mmol) of pentafluorophenol and 8 ml (99 mmol) of pyridine were dissolved. To the solution, 12.9 g (94 mmol) of ethyl chloroglyoxylate were added dropwise under an ice bath for the reaction. After 1 hour stirring at room temperature, the reaction mixture was filtered and concentrated. The thus obtained crude product was refined by distillation to obtain 13.5 g of pentafluorophenyl ethyl oxalate (colorless liquid). The compound had a melting point of 70 to 71° C./2 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:29])([C@H:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[N:26][NH:27][CH:28]=2)=[CH:20][CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[Cl:30]N1C(=O)CCC1=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:29])([C@H:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[NH:25][N:26]=[N:27][C:28]=2[Cl:30])=[CH:20][CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](c1ccc(-c2c[nH]nn2)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2[nH]nnc2Cl)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A solution of (2R,3S)-2-(2,4-difluorophenyl)-3-(4-[1,2,3-triazol-4-yl]phenyl)-1-(1,2,4-triazol-1-yl)butan-2-ol (2.0 g, 5 mmol-a product of Example 66) in dichloromethane (100 ml) was treated with N-chlorosuccinimide (0.81 g, 6 mmol). The mixture was stirred and irradiated at room temperature for 3 days then evaporated to dryness under reduced pressure. The residue was partitioned between ethyl acetate(50 ml) and saturated sodium bicarbonate (20 ml). The organic layer was washed with brine (20 ml), dried (Na2SO4) and evaporated to dryness under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:23]([O:29][CH2:30][CH3:31])(=[O:28])[CH2:24]C([O-])=O.Cl>O1CCCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH2:24][C:23]([O:29][CH2:30][CH3:31])=[O:28])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1ccc(Cl)s1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(Cl)s1
Reaction time: 6 h

Procedure:
To a solution of 5-chlorothiophene-2-carboxylic acid (10.12 g, 62.24 mmol) in tetrahydrofuran (80 ml) was added 1,1′-carbonyldiimidazole (11.1 g, 68.5 mmol) at room temperature and the mixture was stirred as it was for 6 hrs. Monoethyl malonate monomagnesium salt (9.81 g, 34.2 mmol) was added to this mixture at room temperature and the mixture was stirred at 60° C. for 3 hrs. The reaction solution was diluted with ethyl acetate and water, and acidified with conc. hydrochloric acid. The ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to give the objective substance.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:12]([O-])([O-])=[O:13].[K+].[K+].C[C:19]([CH3:21])=[O:20]>>[CH3:11][O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH2:21][C:19]([O:13][CH3:12])=[O:20]
Reactant: O=C([O-])[O-]
Reactant: CC(C)=O
Reactant: COC(=O)c1ccccc1O
Agent: [K+]
Product: COC(=O)COc1ccccc1C(=O)OC
Yield: 17 %

Procedure:
To a mixture of methyl salicylate (100 grams, 657 mmol), anhydrous K2CO3 (360 grams, 2.605 mol) in anhydrous acetone (1000 mL) was added methyl chloro acetate (94 grams, 866 mmol) and refluxed for 36 hours. Acetone was distilled and water (1200 mL) was added. Crude 5 was extracted into Chloroform, dried over Na2SO4 distilled and purified by column chromatography on silica gel using Hexane as eluant to give pure 5 (25 grams, 17%) as a light yellow syrup. The structure was confirmed by NMR. IHNMR (CDCl3) δ 3.79(s, 3H,ester), 3.88(s,3H,ester), 4.70(s,2H,OCH2), 6.88(dd,1H, Ar), 7.03 (m,1H,Ar), 7.42(m,1H,Ar), 7.81(dd,1H,Ar).
Reaction SMILES: [C:1]([C:3]1[C:7]([CH:8]=[CH2:9])=[CH:6][N:5]([CH:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]2(Cl)[Cl:20])[N:4]=1)#[N:2].[Cl:22][C:23](Cl)([Cl:27])[C:24](Cl)=[O:25].P(Cl)(Cl)([Cl:31])=O>C(OCC)C.[Zn]>[C:1]([C:3]1[C:7]([CH:8]2[CH2:9][C:24](=[O:25])[C:23]2([Cl:27])[Cl:22])=[CH:6][N:5]([C:10]2[C:15]([Cl:31])=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][C:11]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: O=P(Cl)(Cl)Cl
Reactant: C=Cc1cn(C2C=CC(C(F)(F)F)=CC2(Cl)Cl)nc1C#N
Agent: [Zn]
Solvent: CCOCC
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC(=O)C1(Cl)Cl
Temperature: 25 °C
Yield: 57 %

Procedure:
3-Cyano-1-(2,2-dichloro-4-trifluoromethylphenyl)-4-vinylpyrazole (5.00 g, 15.06 mmol, WO97/07102-A1) was dissolved in anhydrous diethyl ether (50 ml) in a dry, nitrogen-flushed flask. Activated zinc (2.97 g, 45.8 mmol) was added and the suspension was vigorously stirred. A mixture of trichloroacetyl chloride (3.57 ml, 37.65 mmol) and phosphorus oxychloride (4.1 ml, 37.65 mmol) in diethyl ether (20 ml) was added dropwise at room temperature via a pressure-equalising dropping funnel over a period of 30 minutes--the resulting exotherm being controlled by the rate of addition. On completion of addition, the mixture was heated to reflux for 4 hr then cooled to room temperature. The mixture was filtered and poured onto 200 ml of crushed ice before extracting with diethyl ether (3×100 ml). The combined organics were washed successively with saturated aqueous NaHCO3 solution and brine before drying over MgSO4, filtering, and evaporating the ether in vacuo to leave a black oil. This was purified by silica chromatography (eluting with 10% diethyl ether/hexane) to give 3.80 g of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[O:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[CH:27]([CH3:29])[NH:26][CH2:25][CH2:24]3)=[CH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[C:19]([C:16]5[CH:17]=[CH:18][O:14][CH:15]=5)[CH:20]=[CH:21][CH:22]=4)[CH:27]3[CH3:29])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cccc(-c3ccoc3)c21
Product: CC1c2c(cccc2-c2ccoc2)CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-Furan-3-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)C.CO.O1CCCC1.O.[OH-].[Li+]>O>[F:14][C:13]([F:15])([F:16])[C:10]1[CH:11]=[CH:12][C:7]([NH:6][CH2:5][C:4]([OH:17])=[O:3])=[CH:8][CH:9]=1
Reactant: CCOC(=O)CNc1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CNc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a stirred solution of (4-trifluoromethyl-phenylamino)-acetic acid ethyl ester (0.37 g, 1.5 mmol) in a mixed solvent of methanol (10 mL), tetrahydrofuran (10 mL), and water (10 mL) was added lithium hydroxide monohydrate (0.25 g, 6 mmol) and the mixture was stirred at room temperature overnight. The organic solvent was removed under reduced pressure and the aqueous solution was acidified with solid citric acid to pH˜4, and extracted with ethyl acetate (4×40 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated to give 0.33 g of the crude title compound that was used direct for the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ: 12.68 (s, 1H), 7.38 (d, 2H), 6.66 (d, 2H), 3.87 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([C@@H:26]3[CH2:31][CH2:30][CH2:29][NH:28][C:27]3=O)=[N:14][C:15]=2[C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH:10]=[CH:11][N:12]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:48])=CC=1.C(Cl)Cl.C1COCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([C@@H:26]3[CH2:31][CH2:30][CH2:29][NH:28][C:27]3=[S:48])=[N:14][C:15]=2[C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH:10]=[CH:11][N:12]=1
Reactant: COC(=O)c1ccc(-c2nc([C@@H]3CCCNC3=O)n3ccnc(NCc4ccc(OC)cc4OC)c23)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2nc([C@@H]3CCCNC3=S)n3ccnc(NCc4ccc(OC)cc4OC)c23)cc1
Yield: 62 %

Procedure:
To a solution of (S)-methyl 4-(8-((2,4-dimethoxybenzyl)amino)-3-(2-oxopiperidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)benzoate (940 mg, 1.82 mmol) in toluene (25 mL) was added Lawesson's reagent (1.5 g, 3.65 mmol). The mixture was heated to reflux overnight. The solvent was evaporated and the residue was purified by column chromatography on silica gel eluted with EA:DCM:THF=1:2:1 to give (S)-methyl 4-(8-((2,4-dimethoxybenzyl)amino)-3-(2-thioxopiperidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)benzoate (600 mg, yield 62%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([C:11]2[N:12]=[C:13]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:14]3[S:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[C:6]([F:26])[CH:5]=1.[OH:27][CH2:28][C:29](O)=[O:30].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>O.CN(C=O)C.C(N(CC)CC)C>[ClH:3].[Cl:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([C:11]2[N:12]=[C:13]([N:20]3[CH2:21][CH2:22][N:23]([C:28](=[O:27])[CH2:29][OH:30])[CH2:24][CH2:25]3)[C:14]3[S:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[C:6]([F:26])[CH:5]=1
Reactant: Fc1cc(-c2nc(N3CCNCC3)c3sccc3n2)c(F)cc1Cl
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CO)N1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 185.7 %

Procedure:
A mixture of 500 mg of 2-(4-chloro-2,5-difluorophenyl)-4-piperazine-1-ylthieno[3,2-d]pyrimidine dihydrochloride, 104 mg of hydroxyacetic acid, 0.32 ml of triethylamine, 184 mg of HOBt, 261 mg of EDCI and 10 ml of DMF was stirred for two days at room temperature. 70 ml of water was added to the reaction mixture. After the precipitate was filtered and washed with water, it was dried at 50° C. under reduced pressure. The obtained solid was dissolved in 10 ml of THF and was added to 2 ml of 4M HCl-dioxane aq. The resultant was concentrated under reduced pressure to give a solid. This solid was recrystallized from EtOH-EtOAc to give 487 mg of 2-{4-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperazine-1-yl}-2-oxoethanol hydrochloride.
Reaction SMILES: IC.[C:3]1([C@:9]2([CH2:21][NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:11][C@H:10]2[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:32](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:32][N:22]([CH2:21][C@@:9]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:11][C@H:10]1[CH2:12][O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24]
Reactant: O=S(=O)(NC[C@@]1(c2ccccc2)C[C@H]1COCc1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C[C@@]1(c2ccccc2)C[C@H]1COCc1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
Iodomethane (2.12 g, 14.9 mmol, 4 eq) was added portionwise to N-[((1S,2R)-1-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropyl)methyl]benzenesulfonamide (1.71 g, 3.74 mmol, 1 eq), accessed via the method of preparation 5A, in 7 mL DMF with potassium carbonate (1.03 g, 7.48 mmol, 2 eq) over 6 h at 80° C. Following addition, the reaction mixture was stirred 16 h at 80° C. The reaction mixture was diluted with EtOAc, washed successively with saturated aqueous NaHCO3, water (4×) and brine, dried over MgSO4, filtered and concentrated to give a brown oil. The crude material was purified by flash chromatography (SiO2, eluted successively with hexanes and EtOAc/hexanes (1:4)) to give the title product (1.57 g, 100%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.58-7.19 (m, 15H), 4.57 (ABq, J=24.3, 11.9 Hz, 2H), 3.84-3.80 (m, 1H), 3.58-3.48 (m, 1H), 3.29 (d, J=14.1 Hz, 1H), 2.50 (s, 3H), 1.47 (m, 1H), 1.33 (m, 1H), 0.91 (m, 1H). ES-LCMS m/z 444.2 (M+Na).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[C:6]([CH3:24])=[N:7][C:8]2[C:13]([CH:14]=1)=[C:12]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:11]=[CH:10][N:9]=2)[CH3:3].O.[C:26]([OH:30])(=[O:29])[CH:27]=[O:28].FC(F)(F)C(O)=O.Cl>C(=O)(O)[O-].[Na+].O.C(O)(=O)C>[OH2:4].[OH2:28].[ClH:1].[CH2:2]([O:4][C:5]1[C:6]([CH:24]=[CH:27][C:26]([OH:30])=[O:29])=[N:7][C:8]2[C:13]([CH:14]=1)=[C:12]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH:11]=[CH:10][N:9]=2)[CH3:3]
Reactant: O=CC(=O)O
Reactant: CCOc1cc2c(Nc3ccc(OC)cc3)ccnc2nc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOc1cc2c(Nc3ccc(OC)cc3)ccnc2nc1C=CC(=O)O
Temperature: 95 °C

Procedure:
A mixture of 3-ethoxy-5-(4-methoxyanilino)-2-methyl-1,8-naphthyridine hydrochloride (5.0 g), glyoxylic acid monohydrate (2.2 g) and glacial acetic acid (50 ml) were stirred and treated dropwise with trifluoroacetic acid (12.5 ml). The mixture was stirred and heated at 95° C. for 22 hours and cooled to ambient temperature. The mixture was filtered and the solid obtained was stirred in sodium bicarbonate solution (100 ml) for 15 minutes. The mixture was filtered. The solid obtained was stirred in water (100 ml) and acidified with concentrated hydrochloric acid to pH 1. After stirring for an hour the mixture was filtered to give a solid. The filtrate was evaporated to dryness and the residue triturated with water and filtered. The crops of solid were combined, dissolved in dichloromethane/methanol, dried, filtered and evaporated. The residue was triturated with hot ethyl acetate and hot filtered. The solid obtained was combined with the solid obtained from the acidic mixture above, triturated with hot ethyl acetate and hot filtered. The solid obtained was purified by flash column chromatography on silica using a mixture of ethyl acetate:dichloromethane:methanol, 5:5:1 and then 1:1:1 to give a solid. The solid was triturated with hot ethyl acetate and hot filtered to give 3-[3-ethoxy-5-(4-methoxyanilino)-1,8-naphthyridin-2-yl]acrylic acid hydrochloride dihydrate, m.p. 230°-235° C. (with decomposition).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[CH:22])=[N:19][CH:20]=2)=[CH:11][CH:10]=1.Br[C:24]1[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:26][C:25]=1[Cl:38]>CN(C=O)C.CCOC(C)=O.[Cu]I>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:24]3[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:26][C:25]=3[Cl:38])=[N:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: Clc1cc(OCCN2CCCC2)ccc1Br
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)cc3Cl)nc2)cc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere 0.13 mL (1.00 mmol) triethylamine, 22 mg (0.02 mmol) tetrakis-triphenylphosphane-palladium and 3.7 mg (0.02 mmol) CuI are added successively to a solution of 80 mg (0.37 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine and 114 mg (0.37 mmol) 1-[2-(4-bromo-3-chloro-phenoxy)-ethyl]-pyrrolidine in 3.0 mL DMF. The mixture is stirred for 15 min at 100° C. and at 200 W in the microwave. The reaction solution is diluted with 40 mL EtOAc, washed twice with semisaturated NaHCO3 solution and the organic phase is dried over MgSO4. The solvent is eliminated i.vac. and the residue is triturated with tert-butylmethylether. The solvent is eliminated i.vac. and further purification is carried out by column chromatography with HPLC-MS.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[C:8]([I:10])[CH:9]=1)=[O:4].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>>[I:10][C:8]1[CH:9]=[C:5]([C:3]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:4])[NH:6][CH:7]=1
Reactant: O=C(c1cc(I)c[nH]1)C(Cl)(Cl)Cl
Reactant: OCc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)c1cc(I)c[nH]1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)ethanone (4.0 g, 12 mmol), benzyl alcohol (9.0 mL, 87 mmol), and triethylamine (2.5 mL, 18 mmol) in a round flask was heated at 60° C. with stirring for 2 h. After cooling, the volatiles were removed under reduced pressure to afford the crude product which was directly used in the next reaction without further purification.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[I:15][C:16]1[CH:21]=[C:20]([I:22])[CH:19]=[C:18]([I:23])[C:17]=1[OH:24]>C(#N)C>[C:1]([O:24][C:17]1[C:16]([I:15])=[CH:21][C:20]([I:22])=[CH:19][C:18]=1[I:23])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Oc1c(I)cc(I)cc1I
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: CC#N
Product: CCCCCCCCCCCC(=O)Oc1c(I)cc(I)cc1I
Yield: 83.1 %

Procedure:
Dodecanoyl chloride (2.95 ml, 12.8 mmol) was added to a suspension of 2,4,6-triiodophenol (6.0 g, 12.7 mmol) in refluxing acetonitrile (50 ml) and the mixture was heated under argon for 24 hrs. The reaction mixture was cooled and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness under vacuum to give an off-white solid. The crude product was recrystallized from methanol to give 6.9 g (83%) of the desired ester, mp 68°-69° C.
Reaction SMILES: [Br-].[OH:2][CH2:3][CH2:4][C:5]1[CH:30]=[CH:29][C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][CH:6]=1.[CH:31]([C:33]1[N:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]2)=[CH:35][CH:34]=1)=O>>[OH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:9]=[CH:31][C:33]2[N:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)=[CH:35][CH:34]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)nc2)CC1
Reactant: OCCc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=Cc3ccc(CCO)cc3)nc2)CC1

Procedure:
By a method similar to Production Example 108, step 4, [4-(2-hydroxyethyl)benzyl](triphenyl)phosphonium bromide (2.866 g, 6.004 mmol) and tert-butyl 4-(6-formylpyridin-3-yl)piperazine-1-carboxylate (1.458 g, 5.003 mmol) were condensed to give tert-butyl 4-(6-{2-[4-(2-hydroxyethyl)phenyl]vinyl}pyridin-3-yl)piperazine-1-carboxylate (5.684 g, quantitatively) as a colorless oil.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.N1C=CC=CC=1.Cl>O1CCOCC1>[N:22]1[CH:23]=[CH:24][C:19]([C:18]([N:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)=[O:25])=[CH:20][CH:21]=1
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C1Nc2ccccc2N(C(=O)c2ccncc2)c2ccccc21
Temperature: 0 °C

Procedure:
A mixture of 21.0 g (0.1 mol) of 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 23.0 g (0.129 mol) of isonicotinic acid chloride hydrochloride, 21 ml (0.26 mol) of pyridine and 300 ml of anhydrous dioxan was refluxed for 3 hours. After cooling, the mixture was poured into 1 liter of ice-cold water, acidified with conc. hydrochloric acid and extracted twice, each time with 200 ml of dichloromethane. The aqueous phase was made alkaline with methylene chloride. The combined methylene chloride extracts were washed with water, dried over sodium sulphate and the solvent was removed in vacuo. The residue was recrystallized from hot methanol. After washing with ether, the beige crystals melted at 277°-279° C. Yield 16.0 g (51% of theory).