Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([O:14][CH3:15])[CH:8]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=1>ClCCCl.ClC(Cl)C.[Cl-].[Zn+2].[Cl-]>[F:13][C:11]1[CH:10]=[C:9]([O:14][CH3:15])[CH:8]=[C:7]([OH:6])[C:12]=1[C:25](=[O:26])[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: COc1cc(F)cc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: COc1ccc(CC(=O)c2c(O)cc(OC)cc2F)cc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To 1,2-dichloroethane (40 mL) were added anhydrous aluminum chloride (4.27 g) and zinc chloride (436 mg), followed by stirring 15 min. Under ice-cooling, a solution of 1,3-dimethoxy-5-fluorobenzene (5 g) in 1,2-dichloroethane (15 mL) was added. The mixture was cooled to −10° C. and 4-methoxyphenylacetyl chloride (4.9 mL) in dichloroethane (10 mL) was added drop-wise. The mixture was stirred 30 min at −10° C., and 1 h at room temperature and then heated to reflux for 2 h. The mixture was cooled at 0° C., poured carefully into ice-water and extracted twice with dichloromethane. The dichloromethane layer was dried over MgSO4 and evaporated in vacuo to give the title compound (9.1 g); 1H NMR (CDCl3): 13.23 (s, 1H), 7.17 (d, 2H, J=8.4 Hz), 6.88 (d, 2H, J=8.4 Hz), 6.24 (d, 1H, J=2.1 Hz), 6.18 (dd, 1H, J=13.8 Hz, J′=2.1 Hz), 4.20 (d, 2H, J=3.9 Hz), 3.82 (s, 3H), 3.80 (s, 3H); MS: 291 (MH+); containing 1-(4-fluoro-2-hydroxy-6-methoxyphenyl)-2-(4-methoxyphenyl)ethanone as a by-product. 1H NMR (CDCl3): 13.62 (s, 1H), 7.2–6.0 (6H), 4.29 (s, 2H), 3.90 (s, 3H), 3.81 (s, 3H).
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([CH3:36])[N:19](CC4C=CC=CC=4)[C:20]=3[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:37])(=[O:6])=[O:5])([CH3:3])[CH3:2].[H][H].C[OH:41]>[Pd]>[CH3:1][S:4]([OH:6])(=[O:41])=[O:5].[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([CH3:36])[NH:19][C:20]=3[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:37])(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: CO
Reactant: [H][H]
Reactant: Cc1nc(-c2ccc3nc(N)n(S(=O)(=O)C(C)C)c3c2)c(-c2ccc(F)cc2F)n1Cc1ccccc1
Agent: [Pd]
Product: CS(=O)(=O)O
Product: Cc1nc(-c2ccc3nc(N)n(S(=O)(=O)C(C)C)c3c2)c(-c2ccc(F)cc2F)[nH]1
Yield: 47 %

Procedure:
To a solution of 1-isopropylsulfonyl-2-amino-6-(1-(benzyl)-2-(methyl)-5-(2,4-difluorophenyl)-imidazol-4-yl)-benzimidazole (390 mg, 0.75 mmol) in 100 mL methanol add palladium black (390 mg), and hydrogen gas at 50° C. overnight at 60 psi. The solution is filtered and purified by radial chromatography eluting with 8% methanol in methylene chloride to yield 152 mg (47%) of the title compound as an off-white solid. MS(ES+): m/z=432.0 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl.[C:11]1(Cl)[C:17](=O)C(Cl)=C(Cl)[C:13](=O)[C:12]=1Cl.C(=O)/C=C/C>CC(O)CC.O>[F:9][C:8]1[CH:7]=[C:6]2[C:4](=[CH:3][C:2]=1[F:1])[N:5]=[C:12]([CH3:13])[CH:11]=[CH:17]2
Reactant: Nc1ccc(F)c(F)c1
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: C/C=C/C=O
Agent: Cl
Solvent: O
Solvent: CCC(C)O
Product: Cc1ccc2cc(F)c(F)cc2n1

Procedure:
25.0 g of 3,4-difluoroaniline are dissolved in 120 of 2-butanol. 50 ml of a saturated solution of hydrogen chloride in 2-butanol are added slowly and afterwards 47.6 g (0.1936 mol) of p-chloranil are also added. With a good stirring and at reflux temperature (100-110° C.) a solution of 19.4 ml (0.236 mol) of crotonaldehyde in 45 ml of butan-2-ol is dropped slowly (ca. 2 hr). The whole is refluxed for two additional hours and then evaporated to dryness. The residue is taken with excess THF and is filtered and washed thoroughly with THF until the filtering appears to be uncoloured. The solid thus obtained is solved in water, filtered from some solid impurities and washed with ethyl ether. The aqueous layer is made slightly alkaline with 2N NaOH solution and then extracted with diethyl ether. The ethereal layer is dried and treated with a little decolourising charcoal. After evaporation a white solid is obtained (22.7 g, 65%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])=O)(C)(C)C.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[N+:21]([C:19]1[CH:18]=[CH:17][C:16]([C:24]([F:30])([F:29])[C:25]([F:26])([F:27])[F:28])=[C:15]([CH:20]=1)[O:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)([O-:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cc([N+](=O)[O-])ccc1C(F)(F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OC[C@@H]2CCCN2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in CH2Cl2 (5 mL), TFA (2.5 mL) was added and stirred at RT for 1 h. The mixture was diluted with CH2Cl2 (20 mL) and neutralized with sat NaHCO3 and then 2N NaOH. The mixture was transferred to a seperatory funnel and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with MgSO4, filtered and concentrated in vacuo to yield the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:43][C:44]([NH2:46])=[O:45]>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:43][C:44]([NH2:46])=[O:45])[C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC(N)=O)C(=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (19 mg, 0.04 mmol) in dry DMF (1 mL) was added potassium carbonate (12 mg, 0.08 mmol) and 2-chloroacetamide (12 mg, 0.12 mmol) at room temperature under nitrogen. The reaction mixture was stirred overnight at room temperature and concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel chromatography (gradient 0 to 80% AcOEt in hexane) to give the title compound (14 mg, 67%). 1H NMR (500 MHz, CDCl3): 7.32 (1H, s), 7.28-7.23 (7H,m), 7.16-7.14 (2H,m), 6.22 (1H, br s), 5.65 (1H, br s), 5.09 (1H, br s), 4.94 (2H, s), 4.52 (2H,s), 2.55-2.25 (4H, m), 2.09-2.01 (1H, m), 1.85-1.76 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: Cl[C:2]1C=C(SC2C3C(=CC(C)=CC=3)NC=2CCC(N)=O)C=C(Cl)C=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([OH:45])=[O:44])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.CO>C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([O:45][CH3:2])=[O:44])=[CH:30][CH:31]=1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Reactant: Cc1cccc2[nH]c(C(=O)O)c(Sc3ccc(Cl)cc3)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1[nH]c2cccc(C)c2c1Sc1ccc(Cl)cc1
Yield: 81 %

Procedure:
Following the method used to prepare 24a, the use of 1a (0.19 mmol) and oxalyl chloride in THF followed by allowing the intermediate acid chloride to react with MeOH (3 mL) provided 52 mg (81%) of product 9 as a white solid, mp 192-193° C. 1H NMR (300 MHz, DMSO-d6) δ 2.57 (s, 3H), 3.84 (s, 3H), 6.88 (d, J=7 Hz, 1H), 6.95-6.98 (m, 2H), 7.24 (t, J=8 Hz, 1H), 7.26-7.29 (m, 2H), 7.41 (d, J=9 Hz, 1H), 12.52 (s, 1H). LC-MS (CI): m/z 332.1 [(M+H)+ C17H14ClNO2S requires 331.04]. Purity (100%). Calcd for C17H14ClNO2S: C, 61.53; H, 4.25; N, 4.22; S, 9.66; Cl, 10.68. Found: C, 61.25; H, 4.24; N, 4.14; S, 9.56; Cl, 10.64.
Reaction SMILES: [C:1]1(S)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]1[S:13][CH:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=1>CN(C)C=O>[C:1]1([C:9]2[S:13][CH:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: O=C(O)c1csc(Br)c1
Solvent: CN(C)C=O
Product: O=C(O)c1csc(-c2ccccc2)c1
Temperature: 135 °C

Procedure:
In an open flask, thiophenol (2.86 g., 13 mmoles), cuprous oxide (1.86 g., 13 mmoles) and dimethyl formamide (30 ml.) were combined and heated in a 135° C. oil bath. The reaction mixture was allowed to cool slightly, 5-bromothiophene-3-carboxylic acid [2.5 g., 13 mmoles; Fournari et al., Bull. Chim. Soc. Fr., 4115 (1967)] in 50 ml. of dimethylformamide was added, and the mixture refluxed for 2 days. The reaction mixture was cooled, clarified by filtration, the filtrate evaporated to an oil, the oil triturated with 1 N hydrochloric acid, and gummy solids recovered by filtration and taken up in 1 N sodium hydroxide. The basic solution was extracted with ether, reacidified with conc. hydrochloric acid, product recovered by filtration, triturated with hexane and refiltered (912 mg., m.p. 97°-100° C., m/e 220). Recrystallization from methanol/water afforded purified 5-phenylthiofuran-3-carboxylic acid (439 mg., m.p. 101°-103° C.).
Reaction SMILES: [C:1]1([CH:11]([N:13]2[CH:17]3[C:18](=O)[N:19]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:21][CH:16]3[CH2:15][CH2:14]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C1COCC1>[C:1]1([CH:11]([N:13]2[CH:17]3[CH2:18][N:19]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:21][CH:16]3[CH2:15][CH2:14]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(c1cccc2ccccc12)N1CCC2CCN(CCc3ccccc3)C(=O)C21
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(c1cccc2ccccc12)N1CCC2CCN(CCc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
To a solution of 4 (4.8 g, 12 mmol) in THF (100 mL) is added slowly 1 M DIBAL in toluene, (50 mL, 50 mmol) at −78° C. The mixture is stirred at room temperature for 1 hour and quenched with 20 mL of water. The solvent is evaporated, the residue is diluted with 100 mL of 1:1 saturated Rochells salt/15% NaOH, and this extracted with EtOAc (4×50 mL). The organic extracts are combined, dried and concentrated under vacuum. The residue is purified by flash chromatography (silica gel; Hexane/EtOAc 1:9) to provide 2.3 g (48%) of the title compound. M+H+=385.26.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:15]1[CH2:20][CH2:19][CH:18]=[CH:17][CH2:16]1.Cl>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:15]2[CH2:20][CH2:19][CH:18]=[CH:17][CH2:16]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C1=CCNCC1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: Cl
Solvent: O
Product: O=C(O)c1cc(S(=O)(=O)N2CC=CCC2)ccc1Cl
Temperature: 25 °C

Procedure:
2-Chloro-5-chlorosulfonylbenzoic acid (25.5 g.) is added in small portions over a 5 minute period with cooling to a solution of 1,2,5,6-tetrahydropyridine (25.0 g.) in 200 ml. of water. After stirring at room temperature for a half hour, the reaction mixture is acidified with concentrated hydrochloric acid. The crystalline precipitate is filtered off and dissolved in 75 ml. of methylene chloride and 10 ml. of ether. After concentration to 50 ml., hexane is added to turbidity, affording crystals, m.p. 180°-182° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C:11]([CH3:16])([C:13]([OH:15])=O)[NH:10][C:9]2=[O:17])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([NH:24][C:13]([C:11]2([CH3:16])[CH2:12][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9](=[O:17])[NH:10]2)=[O:15])=[CH:26][C:27]=1[C:33]([F:34])([F:35])[F:36])#[N:30]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CC1(C(=O)O)CN(c2ccc(F)cc2)C(=O)N1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)CN(c2ccc(F)cc2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
A solution of 1-(4-fluoro-phenyl)-4-methyl-2-oxo-imidazolidine-4-carboxylic acid (120 mg, 0.50 mmol) in DCM (15 mL) was treated oxalyl chloride (0.09 mL, 1.03 mmol) and one drop of dry DMF. After stirring 1 hour at room temperature, the solvent was removed in vacuo. To this residue, a solution of 4-amino-2-(trifluoromethyl)benzonitrile (277 mg, 1.49 mmol) and triethylamine (0.28 mL, 2.01 mmol) in dry DCM (10 mL) was added. After stirring overnight at room temperature, the mixture was concentrated in vacuo and the residue purified by flash chromatography to afford the title compound as a tan solid (110 mg, 54%).
Reaction SMILES: [CH3:1][C:2]([OH:10])([CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH:11]12[CH:20]3[CH2:21][CH:17]([CH:18]=[CH:19]3)[CH:16]1[CH:15]1[CH2:22][CH:12]2[CH:13]([CH2:23][CH2:24][C:25](OC)=[O:26])[CH2:14]1>>[CH:11]12[CH:20]3[CH2:21][CH:17]([CH:18]=[CH:19]3)[CH:16]1[CH:15]1[CH2:22][CH:12]2[CH:13]([CH2:23][CH2:24][C:25]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([OH:10])([CH3:1])[CH2:8][CH3:9])=[O:26])[CH2:14]1
Reactant: COC(=O)CCC1CC2CC1C1C3C=CC(C3)C21
Reactant: CCC(C)(O)CCCCO
Product: CCC(C)(O)CCCCOC(=O)CCC1CC2CC1C1C3C=CC(C3)C21
Yield: 87 %

Procedure:
By following the procedure of Synthesis Example 2 except that 5-methyl-1,5-heptanediol was used instead of 4-methyl-1,4-pentanediol and methyl 3-(8-tetracyclo-[4.4.0.12,5.17,10]dodecen-3-yl)propionate used instead of methyl 5-norbornene-2-carboxylate, there was obtained 5-hydroxy-5-methylheptyl 3-(8-tetracyclo[4.4.0.12,5.17,10]-dodecen-3-yl)propionate. Yield 87%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=[O:12])[NH:7][CH:8]=[CH:9][C:10]=2[CH:11]=1.CO.C(#N)C.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2.[F:34][B-](F)(F)F.CCO[C:42](C)=[O:43]>O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=[O:12])[NH:7][CH:8]([O:43][CH3:42])[CH:9]([F:34])[C:10]=2[CH:11]=1
Reactant: F[B-](F)(F)F
Reactant: CCOC(C)=O
Reactant: O=c1[nH]ccc2cc(Cl)cnc12
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CO
Solvent: CC#N
Solvent: O
Product: COC1NC(=O)c2ncc(Cl)cc2C1F
Temperature: 47.5 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A pressure bottle was charged with 3-chloro-1,7-naphthyridin-8(7H)-one (Anichem, 15 g, 83 mmol), MeOH (34 ml), acetonitrile (173 ml) and 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (Aldrich, 30.9 g, 87 mmol). The mixture was heated to 45-50° C. After 6 hs additional 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (2.5 g) was added and heating was continued overnight. Water and EtOAc were added to the cooled reaction mixture and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was triturated with EtOAc. The solid was filtered off and the title compound (15.34 g, 66.5 mmol, 80% yield) was isolated as a white solid. MS m/z=231 [M+H]+. Calculated for C9H8ClFN2O2: 230.0
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1n[nH]cc1-c1ccccn1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)c(Cl)c1
Product: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc2c(-c3ccccn3)cnn12
Yield: 54.5 %

Procedure:
Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (285 mg, 1.0 mmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 3-amino-4-(2-pyridinyl)-pyrazole [CAS No. 493038-87-2; prepared from 2-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (223 mg, 55%). MS (ISP) 409.2 [(M+H)+]; mp 188° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].C[OH:5].C(C1CN([C:12](=[O:47])[C@H:13]([NH:17][C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]4[S:37][C:36]5[C:31](=[N:32][CH:33]=[CH:34][C:35]=5Cl)[CH:30]=4)[N:27]=3)[N:22]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:21]=2)=[O:19])[CH:14]2[CH2:16][CH2:15]2)C1)#N>>[CH:14]1([C@@H:13]([NH:17][C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]4[S:37][C:36]5[C:31](=[N:32][CH:33]=[CH:34][C:35]=5[O:2][CH3:1])[CH:30]=4)[N:27]=3)[N:22]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:44])[CH3:45])[CH:21]=2)=[O:19])[C:12]([OH:5])=[O:47])[CH2:15][CH2:16]1
Reactant: C[O-]
Reactant: CO
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cc4nccc(Cl)c4s3)cnc21
Agent: [Na+]
Product: COc1ccnc2cc(-c3cnc4c(n3)c(C(=O)N[C@@H](C(=O)O)C3CC3)cn4COCC[Si](C)(C)C)sc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of sodium methoxide in MeOH (0.5 M, 0.97 mL, 0.49 mmol) was added 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (35 mg, 0.056 mmol) and reaction mixture was stirred at 100° C. for 1 h under microwave assisted conditions. The reaction mixture was evaporated to dryness and the crude residue was purified by preparative TLC (CH2Cl2:MeOH:NH4OH, 80:19:1) to give 18 mg (57%) of (R)-cyclopropyl-{[2-(7-methoxy-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-acetic acid. MS: (M+H)+=554; (M−H])−=552.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([CH2:15][CH2:16][C:17](N(OC)C)=[O:18])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[Mg]Br.O1CCCC1.[Cl-].[NH4+].O>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([CH2:15][CH2:16][C:17]([C:24]4[S:23][CH:27]=[CH:26][CH:25]=4)=[O:18])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CON(C)C(=O)CCc1nnc(-c2ccc3c(c2)CCO3)o1
Reactant: Br[Mg]c1cccs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCc1nnc(-c2ccc3c(c2)CCO3)o1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
To a solution of 3-[5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]-N-methoxy-N-methylpropionamide (2.50 g, 8.24 mmol) in tetrahydrofuran (50 mL) was added 1 M (2-thienyl)magnesium bromide-tetrahydrofuran solution (9.9 mL, 9.9 mmol), and the resulting mixture was stirred at room temperature for 1 hr. A saturated aqueous ammonium chloride solution (50 mL) and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (1.10 g, yield 41%) as colorless crystals.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[OH-:25].[Na+].[O:27]1[CH2:42][CH:28]1[CH2:29][NH:30][C:31](=[O:41])[C:32]1[C:33](=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:34](N)=[O:35].Cl>O.O1CCOCC1>[C:34]([C:33]1[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=1[C:31](=[O:41])[NH:30][CH2:29][CH:28]([OH:27])[CH2:42][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1)([OH:25])=[O:35]
Reactant: [OH-]
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: NC(=O)c1ccccc1C(=O)NCC1CO1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)CNC(=O)c2ccccc2C(=O)O)CCN(CC(=O)O)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
50 g (144.3 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (D03A) is dissolved in 250 ml of water and the pH is adjusted to 13 with 5 N sodium hydroxide solution. Then, a solution of 38.12 g (187.6 mmol) of N(2,3-epoxypropyl)-phthalamide in 100 ml of dioxane is instilled within one hour, stirred for 24 hours at 50° C. and the pH is kept at 13 by adding 5 N sodium hydroxide solution. The solution is adjusted to pH 2 with 10% hydrochloric acid and evaporated to dryness in a vacuum. The residue is dissolved in some water and purified on an ion-exchange column (Reillex®=poly-(4-vinyl)-pyridine (it is eluted with water). The main fractions are concentrated by evaporation in a vacuum and the residue is given a final purification by chromatography on RP-18 (LiChroPrep®/mobile solvent: gradient of tetrahydrofuran/methanol/water). After concentration by evaporation of the main fractions, 63.57 g (71% of theory) of an amorphous solid is obtained.
Reaction SMILES: CC(=O)C.O.[NH2:6][NH2:7].C(O[CH:11](OCC)[CH:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)=O)C>C(O)C>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:12]1[CH:11]=[N:6][NH:7][C:13]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: NN
Reactant: CCOC(OCC)C(C(=O)c1ccccn1)c1ccccn1
Solvent: CCO
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(-c2cn[nH]c2-c2ccccn2)nc1

Procedure:
The propanone was dissolved in 1 L of ethanol, 5.8 mL (0.12 mol) of hydrazine hydrate was added, and the mixture was heated to reflux for 1 hr. The ethanol was stripped off in vacuo, and the residue was put through a 600 g silica gel column eluting with 1:1 hexane-acetone to yield about 4 g of 4,5-bis(2-pyridinyl)-1H-pyrazole as a light tan solid after removal of solvent.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[O:16][CH2:17][CH3:18].[Li+].[OH-]>C1COCC1.CO>[CH2:17]([O:16][C:7]1[CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=[CH:11][C:6]=1[CH:5]=[CH:4][C:3]([OH:19])=[O:2])[CH3:18]
Reactant: CCOc1cc(C(F)(F)F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(C(F)(F)F)ccc1C=CC(=O)O
Yield: 97.2 %

Procedure:
3-(2-Ethoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (477 mg, 1.74 mmol) was reacted with 1N LiOH (7.5 ml) in THF and CH3OH for 1.5 hrs as described above to yield title compound (440 mg, 97%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15](C=O)[C:16](=O)[C:17](OCC)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:25].[NH2:26][NH2:27]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[C:17]([C:9]([O:8][CH2:1][CH3:2])=[O:25])[NH:26][N:27]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: NN
Reactant: CCOC(=O)C(=O)C(C=O)c1ccc(OCc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)n[nH]1
Temperature: 25 °C

Procedure:
A suspension of ethyl 4-benzyloxyphenyl-2,4-dioxobutanoate (35.86 g) in ethanol (300 mL) is treated with hydrazine hydrate (6 mL) and the mixture is heated at reflux for 2 hours. The reaction mixture is cooled to room temperature, filtered, and the solid washed with ethanol to give ethyl 5-(4-benzyloxyphenyl)-2H-pyrazole-3-carboxylate (25 g), m.p. 160-170° C.