Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[S:14][C:15]=1[C:16](=[O:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([C:11]2[C:12]3[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=3[S:14][C:15]=2[C:16](=[O:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)c1sc2ccccc2c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)c1sc2ccccc2c1-c1ccccc1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of trans-dichlorobis(triphenyl-phosphine)palladium (ii) (0.138 g, 0.196 mmol), phenylboronic acid (0.717 g, 5.88 mmol), 1-(3-bromobenzo[b]thiophen-2-yl)ethanone (0.50 g, 1.960 mmol) and 2.0 N aqueous sodium carbonate (2.94 mL, 5.88 mmol) in Toluene (10 mL) was purged with nitrogen and heated to 110° C. overnight. After 16 h, the reaction mixture was partitioned between EtOAc and water. The organic layer was stirred over MgSO4, filtered and concentrated under reduced pressure to give a red oil. The product was purified by column chromatography on a silica gel column using 20 to 40% gradient of EtOAc in hexane as eluent to give 1-(3-phenylbenzo[b]thiophen-2-yl)ethanone a colorless oil: 1H NMR (400 MHz, CDCl3) δ 2.12 (s, 3H) 7.30-7.35 (m, 1H) 7.38-7.42 (m, 2H) 7.42-7.49 (m, 2H) 7.52-7.58 (m, 3H) 7.87 (d, J=8.2 Hz, 1H); LC-MS (ESI)] m/z 253.1 [M+H]+.
Reaction SMILES: [CH2:1]([NH:7][C:8](=O)[CH3:9])[CH2:2][CH2:3][CH2:4][CH2:5]C.[CH3:11][N:12](C)[C:13](Cl)=O.[OH-].[Na+].C(=O)([O-])[O-].[Ca+2]>ClCCl.C1(C)C=CC=CC=1>[CH3:11][N:12]([CH3:13])[C:8](=[N:7][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH3:9]
Reactant: CCCCCCNC(C)=O
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCN=C(C)N(C)C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
N-Hexyl acetamide (10.0 g, 77.5 mmol) was added 10 mL of dry toluene, then 8.33 g (77.5 mmol) of dimethylcarbamyl chloride was slowly added and then refluxed under a nitrogen atmosphere for 16 h. The volatile materials were removed on a rotary evaporator and then in vacuo at room temperature. The residue was dissolved dichloromethane (30 mL) and 3.1 g (77.5 mmol) of sodium hydroxide dissolved aqueous solution (40 mL) was added. The mixture was stirred vigorously for 30 min. Calcium carbonate (3.1 g) was added to the mixture and it was stirred another 30 min. The organic phase was separated and the aqueous phase was washed with dichloromethane (3×25 mL). The combined organic liquids were dried (calcium carbonate) and the volatile materials were removed on a rotary evaporator. The residue was distilled at 40-41° C./0.25 Torr to yield 4.7 g (39%) of product (98.5% pure by GC). IR (neat) 2956, 2927, 2857 (C—H), 1626 (N═C) cm−1. 1H NMR 3.18 (t, 2H, JHH 7.5 Hz, —CH2—N═), 2.87 (s, 6H, —N—(CH3)2); 1.88 (s, 3H, —N═C(CH3)—N); 1.51 (m, 2H, —CH2—CH2—N═); 1.25-1.4 (m, 4H, CH3—(CH2)2—); 0.90 (t, 3H, JHH 6.9 Hz, CH3). 13C NMR 158.90; 50.35; 38.15; 32.27; 29.98; 22.87; 14.31; 12.53.
Reaction SMILES: C1(C=CC=C(O)C=1)O.C1(C=CC=C(O)C1)O.[CH3:17][CH:18]1[C:23](=[O:24])[CH2:22][CH2:21][CH2:20][C:19]1=[O:25].BrBr.BrC1C=C(Br)C(O)=C(C)C=1O>>[CH3:17][C:18]1[C:19]([OH:25])=[CH:20][CH:21]=[CH:22][C:23]=1[OH:24]
Reactant: CC1C(=O)CCCC1=O
Agent: BrBr
Agent: Cc1c(O)c(Br)cc(Br)c1O
Agent: OC1=CC=CC(O)C1
Product: Cc1c(O)cccc1O

Procedure:
The synthetic routes to an alkylresorcinol that is partially alkylated at a position other than the 4th position on the aromatic ring are multistep and give low overall yields. For example, a 50% yield of a 2-methylresorcinol is obtained by hydrogenation of resorcinol and methylation of the resulting dihydroresorcinol to 2-methylcyclohexane-1,3-dione which on treatment with bromine is converted into 4,6-dibromo-2-methylresorcinol and finally hydrogenolysis of the dibromo derivative to produce the 2-methylresorcinol. Another example is that 5-methylresorcinol can be prepared by a five-step synthesis starting with p-toluidine or a four-step synthesis starting from ethyl crotonate. The five-step synthesis involves acetylation, two-step nitration, reductive hydrogenation, and hydrolysis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([SH:12])[CH:6]=[CH:5]2.I[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].C(O)CO>[Cu]I.O.C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17])[CH:6]=[CH:5]2
Reactant: N#Cc1ccccc1I
Reactant: Sc1ccc2cc(Br)ccc2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: O
Solvent: CC(C)O
Product: N#Cc1ccccc1Sc1ccc2cc(Br)ccc2c1

Procedure:
A mixture of 6-bromo-2-naphthyl hydrosulfide (Step 2, 2.08 g, 8.7 mmol), 2-iodobenzonitrile (2 g, 8.56 mmol), copper(I) iodide (83 mg, 0.44 mmol) and potassium carbonate (2.4 g, 17.4 mmol) was degassed then isopropyl alcohol (10 mL) and ethylene glycol (0.97 mL, 17.4 mmol) added. The reaction was heated to 80° overnight. The cooled reaction mixture was poured into water and extracted with dichloromethane (x3). The combined organic layers were washed with ammonium chloride solution, water and brine, filtered, dried over MgSO4 and evaporated in vacuo to give 2-[(6-bromo-2-naphthyl)thio]benzonitrile (2.85 g, containing some 2,2′-dithiobis(6-bromonaphthalene)). 2.19 g of this was treated according to the method of Example 2 Step 4 to give 2-[(6-bromo-2-naphthyl)sulfonyl]benzonitrile (1.33 g, 56%). 1H NMR (500 MHz, CDCl3) δ 8.76 (1H, s), 8.41 (1H, d, J=8.0 Hz), 8.07 (1H, s), 7.94-7.79 (5H, m), 7.72-7.68 (2H, m); m/z (ES+) 372, 374 [MH+].
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:11]3[CH2:20][CH2:19][CH2:18][CH:12]3[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1)=[O:4].[OH-].[Na+].S(=O)(=O)(O)O>C1COCC1.CO>[C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:11]3[CH2:20][CH2:19][CH2:18][CH:12]3[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1)([OH:4])=[O:2]
Reactant: COC(=O)CCc1ccc2c(c1)NC(=O)C1CCCC21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1ccc2c(c1)NC(=O)C1CCCC21
Yield: 89.8 %

Procedure:
A solution of 4.0 g (14.6 mmol) of 7-(2-methoxycarbonylethyl)-1,2,3,3a,5,9b-hexahydro-cyclopenta[c]quinolin-4-one in 60 ml of THF and 100 ml of methanol is stirred for 24 hours with 29 ml of 1 M aqueous sodium hydroxide solution. The batch is set at pH 5 with 10% sulfuric acid and extracted with dichloromethane and ethyl acetate. The combined extracts are freeze-dried (Na2SO4) and concentrated by evaporation in a vacuum. After column chromatography on silica gel with dichloromethane-methanol, 3.4 g of 7-(carboxyethyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one is isolated.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[CH:29][NH:30]2)=[CH:26][C:25]=1[OH:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[CH:29][NH:30]2)=[CH:26][C:25]=1[O:33][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: Oc1cc2cc[nH]c2cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cc[nH]c4cc3F)ncnc2cc1OCCCN1CCCC1
Yield: 53.3 %

Procedure:
Using an analogous procedure to that described in Example 243, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (213 mg, 0.662 mmol), (prepared as described for the starting material in Example 9), was reacted with 6-fluoro-5-hydroxyindole (120 mg, 0.794 mmol), (prepared as described for the starting material in Example 242), in DMF (3 ml) containing potassium carbonate (137 mg, 0.993 mmol) to give 4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (154 mg, 53%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:7][C:8]2[O:12][C:11]([CH:14]=O)([CH3:13])[CH2:10][C:9]=2[C:16]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2].[C:25]([NH:28][NH2:29])([NH2:27])=[NH:26].Cl>C(O)C.N1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:7][C:8]2[O:12][C:11]([CH:14]=[N:29][NH:28][C:25]([NH2:27])=[NH:26])([CH3:13])[CH2:10][C:9]=2[C:16]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(C=O)O2
Reactant: N=C(N)NN
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(C=NNC(=N)N)O2
Yield: 98.3 %

Procedure:
In a mixed solvent of 20 ml of ethanol and 8 ml of pyridine was dissolved 3.9 g of 5-acetoxy-4,6-di-t-butyl-2-formyl-2-methyl-2,3-dihydrobenzofuran, and 1.42 g of aminoguanidine hydrochloride was added at room temperature. After heating under reflux for 14 hours and then cooling, ethanol and excess pyridine were distilled off using an evaporator, and the concentrate was combined with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography eluting with chloroform containing 10% methanol to give 4.48 g of 1-[(5-acetoxy-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl)methylideneamino]guanidine (rotamer mixture) as a pale yellow oil (yield 99%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Br[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:30][O:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)=[CH:21][CH:22]=1
Reactant: COCCOc1ccc(Br)cc1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COCCOc1ccc(-c2cnc3[nH]ccc3c2)cc1
Yield: 67.8 %

Procedure:
To a solution of 5-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (1.1 g, 4.3 mmol) in tetrahydro ran (40 mL) was added 1-bromo-4-(2-methoxy-ethoxy)-benzene (80, 1.50 g, 6.49 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.25 g, 0.21 mmol). The reaction mixture was stirred with potassium carbonate solution (10 mL, 1.0 M) and warmed to reflux overnight. The biphasic reaction mixture was diluted with ethyl acetate (50 mL) and saturated sodium carbonate solution (20 mL). The organic layer was separated, washed with brine, dried over magnesium sulfate and purified by silica gel column chromatography (50-100% ethyl acetate in hexanes) to give the desired compound as a colorless solid (81, 782 mg, 67%). MS (ESI) [M+H+]+=267.4.
Reaction SMILES: BrC1C=CC(C(N2CCN(C3C(C)=CC(C)=CN=3)CC2)=O)=CC=1.C(C1NC(=O)N(CC2C=CC(OC)=CC=2)C1=O)(C)C.[CH3:43][C:44]1[C:45]([N:51]2[CH2:56][CH2:55][N:54]([C:57]([C:59]3[CH:64]=[CH:63][C:62]([N:65]4[CH:69]([CH:70]([CH3:72])[CH3:71])[C:68](=[O:73])[N:67](CC5C=CC(OC)=CC=5)[C:66]4=[O:83])=[CH:61][CH:60]=3)=[O:58])[CH2:53][CH2:52]2)=[N:46][CH:47]=[C:48]([CH3:50])[CH:49]=1>>[CH3:43][C:44]1[C:45]([N:51]2[CH2:52][CH2:53][N:54]([C:57]([C:59]3[CH:64]=[CH:63][C:62]([N:65]4[CH:69]([CH:70]([CH3:71])[CH3:72])[C:68](=[O:73])[NH:67][C:66]4=[O:83])=[CH:61][CH:60]=3)=[O:58])[CH2:55][CH2:56]2)=[N:46][CH:47]=[C:48]([CH3:50])[CH:49]=1
Reactant: COc1ccc(CN2C(=O)C(C(C)C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cc3)C2=O)cc1
Agent: COc1ccc(CN2C(=O)NC(C(C)C)C2=O)cc1
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C(C)C)cc3)CC2)c(C)c1

Procedure:
Using (4-bromophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (225 mg) described in Preparation Example 165 and 5-isopropyl-3-(4-methoxybenzyl)imidazolidine-2,4-dione (157 mg) described in Preparation Example 209 and by the reaction and treatment in the same manner as in Example 508, the title compound (169 mg) was obtained via 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-5-isopropyl-3-(4-methoxybenzyl)imidazolidine-2,4-dione.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.S(Cl)([Cl:30])(=O)=O>C(Cl)Cl>[Br:1][C:2]1[C:11]2[S:12][C:13]([CH2:16][Cl:30])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: CC(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc(CCl)c(C)c23)cc1
Temperature: 0 °C
Yield: 59.5 %

Procedure:
To a cold (ice bath) solution of acetic acid 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (4.00 g, 9.4 mmol) in anhydrous methylene chloride (41 mL) was added sulfuryl chloride (0.76 mL, 10.3 mmol) dropwise over a period of 10 minutes. After stirring 1 hour in the ice bath the reaction was quenched with water (100 mL) and diluted with diethyl ether. After filtering, the layers were separated. Silica gel was added to the organic layer and the solvents were removed. The adsorbate was flash chromatographed (gradient 90/10-80/20 petroleum ether/ethyl acetate) to give the title compound as a white solid (2.57 g, 59%): NMR (DMSO-d6); δ8.23 (d, J=8 Hz, 1H), 7.71 (dd, J=8,1 Hz, 1H), 7.55-7.43 (m, 4H), 7.33-7.30 (m, 2H), 5.09 (s, 2H), 2.34 (s, 3H), 1.66 (s, 3H).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]([OH:21])(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15].[OH-].[CH2:23]([P+:27]([CH2:36][CH2:37][CH2:38][CH3:39])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26]>CC(C)=O>[C:12]([O-:21])(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15].[CH2:36]([P+:27]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:37][CH2:38][CH3:39].[C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccccc1O
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: O=C(O)C=Cc1ccccc1
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C([O-])c1ccccc1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Cinnamic acid (0.7408 g, 5 mmol), salicylic acid (0.6909 g, 5 mmol) and tetrabutylphosphonium hydroxide (˜40% sol. in H2O) (3.414 g, 5 mmol) were dissolved in 20 ml of acetone stirred and for 15 min at room temperature. The solvent was evaporated and the remaining viscous liquid was dried at 0.1 mbar with stirring for 24 hrs. Identity and purity was confirmed via 1H NMR. The desired compound is isolated as a colourless liquid; 1H-NMR (300 MHz, d6-DMSO) δ(ppm)=7.67 (m, 3H), 7.57 (d, J=19.1 Hz, 1H), 7.41 (m, 3H), 7.12 (m, 1H), 6.56 (m, 3H), 2.17 (m, 8H), 14.1 (m, 16.H), 0.91 (t, J=6.9 Hz, 12 H). 31P-NMR (121.5 MHz, d6-DMSO) δ(ppm)=35.1. 13C-NMR (75 MHz, d6-DMSO) δ(ppm)=171.2, 167.6, 163.0, 143.3, 134.4, 131.1, 130.0, 129.9, 128.9, 128.1, 120.7, 120.0, 115.7, 115.6, 23.3 (d, J=15.9 Hz), 22.6 (d, 4.2 Hz), 17.3 (47.8 Hz), 13.2 (s). Tg−43° C., T5%onset 191° C.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=3)=[CH:28][CH:29]=2)=[O:23])=[CH:16][CH:17]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3cccc(O)c3)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3cccc(O)c3)cc2)cc1)C(=O)O
Yield: 87.9 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[2-(3′-hydroxybiphenyl-4-carbonylamino)ethoxy]phenyl]propionate (350 mg), which is the product of Example 33, was reacted with aqueous sodium hydroxide solution (1N, 2.85 ml) and the reaction mixture was treated to give the title compound (290 mg) as a white powder.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]4[CH2:28][CH2:27][CH2:26][C:12]=4[N:13]=[C:14]([N:16]4[CH2:20][C@H:19]([O:21][CH3:22])[CH2:18][CH:17]4[C:23]([OH:25])=[O:24])[N:15]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH:29]1C=CC2N(O)N=NC=2C=1.O.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]4[CH2:28][CH2:27][CH2:26][C:12]=4[N:13]=[C:14]([N:16]4[CH2:20][C@H:19]([O:21][CH3:22])[CH2:18][CH:17]4[C:23]([O:25][CH3:29])=[O:24])[N:15]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: On1nnc2ccccc21
Reactant: CO[C@@H]1CC(C(=O)O)N(c2nc3c(c(Nc4cc(C5CC5)[nH]n4)n2)CCC3)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CO
Solvent: O
Product: COC(=O)C1C[C@@H](OC)CN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxylic acid (3.5 g, 9.11 mmol) in MeOH (20 mL) was added HOBt.H2O (2.27 g, 4.56 mmol), N-methylmorpholine (2 mL, 18.22 mmol) and EDCI.HCl (2.44 g, 12.75 mmol). The reaction mixture was allowed to stir at RT for 1 h. MeOH was removed under reduced pressure and the residue was dissolved in EtOAc (200 mL). The solution was washed with water (10×100 mL) followed by brine (100 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure afforded (4R)-methyl 1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxylate (3 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2=[N:13][C:14]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[CH:15][C:16](=[O:17])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:34]Br>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([Br:34])[C:10]2=[N:13][C:14]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[CH:15][C:16](=[O:17])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)N1CCc2nc(-c3ccncn3)cc(=O)n2CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(Br)C1
Temperature: -30 °C
Reaction time: 0.08 h
Yield: 46.2 %

Procedure:
To a solution of 4.5 g (14.27 mmol) of 4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester in dry tetrahydrofuran (140 mL) under argon at −30° C. was added 15.70 mL (15.70 mmol) of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran). The solution was stirred at −30° C. for 5 min and 0.77 mL (14.98 mmol) of bromine was added. The reaction was stirred at −30° C. to room temperature during 3 hours. The mixture was quenched with the addition of a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (dichloromethane with 1 to 3% of methanol) to afford 2.6 g (46%) of product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH:28]4[CH2:30][CH2:29]4)=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[O:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36]>>[CH:28]1([C:24]2[CH:25]=[C:26]([CH3:27])[C:21]([N:18]3[CH2:19][CH2:20][N:15]([C:13]([C:5]4[CH:4]=[CH:3][C:2]([N:33]5[CH2:34][CH2:35][O:31][C:32]5=[O:36])=[CH:7][C:6]=4[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[O:14])[CH2:16][CH2:17]3)=[N:22][CH:23]=2)[CH2:30][CH2:29]1
Reactant: O=C1NCCO1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2NS(C)(=O)=O)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCOC3=O)cc2NS(C)(=O)=O)CC1
Yield: 32.1 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using N-{5-bromo-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}methanesulfonamide (247 mg) described in Preparation Example 124 and oxazolidin-2-one (43.5 mg), the title compound (80.1 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: O=C1CCC(c2ccc(O)cc2)=NN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C2=NNC(=O)CC2)cc1
Yield: 80.8 %

Procedure:
A stirred mixture of dry acetone (50 ml), 6-(4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (7 g, 0.037 mole), allyl bromide (3.2 ml, 0.037 mole) and potassium carbonate (5.1 g, 0.037 mole) was heated under reflux for 14 hours. The mixture was diluted with acetone and filtered hot. The inorganic residue was washed with warm acetone and the combined washings and filtrate were evaporated under reduced pressure. The residue was broken up with ether, collected and washed with ether to give 6-(4-allyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (6.88 g, 81%, m.p. 130.5°-132°C). Recrystallisation from methanol gave fine white needles of m.p. 134°-135°C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([S:25]([CH3:27])=[O:26])=[CH:9]2)=[N:6][CH:7]=1.[O:28]1[C:32]2[CH:33]=[CH:34][C:35](B(O)O)=[CH:36][C:31]=2[O:30][CH2:29]1>>[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([C:2]3[CH:3]=[N:4][C:5]([N:8]4[C:16]5[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]6[CH2:24][CH2:23][O:22][CH2:21][CH2:20]6)=[O:18])[CH:15]=5)[C:10]([S:25]([CH3:27])=[O:26])=[CH:9]4)=[N:6][CH:7]=3)=[CH:36][C:31]=2[O:30][CH2:29]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CS(=O)c1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Product: CS(=O)c1cn(-c2ncc(-c3ccc4c(c3)OCO4)cn2)c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
Prepared from (1-(5-bromopyrimidin-2-yl)-3-(methylsulfinyl)-1H-indol-6-yl)(morpholino)-methanone (0.3 g, 0.67 mmol) and benzo[1,3]dioxole-5-boronic acid (0.22 g, 1.33 mmol) analogously to synthesis example 261. White solid. Yield: 0.145 g (44% of theory)