Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([O:5][CH2:6][C:7]#[CH:8])(C)C.C([Mg]Br)C.[CH2:13]([N:20]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][CH2:23][C:22]([C:8]#[C:7][CH2:6][OH:5])([OH:26])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: C#CCO[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[Mg]Br
Agent: [F-]
Solvent: C1CCOC1
Product: OCC#CC1(O)CCCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
O-Trimethylsilylpropargyl alcohol (15.4 ml, 100 mmol) was added slowly at 0 to 5° C. to a cooled (0° C.) solution of ethylmagnesium bromide (1 M in tetrahydrofuran, 100 ml, 100 mmmol) in tetrahydrofuran. The reaction mixture was stirred at 0° C. for 15 minutes and then allowed to warm to room temperature over 30 minutes (exotherm and gas evolution observed), before recooling to 0° C. To this was added a solution of 1-benzyl-3-piperidone (15.16 g, 80.1 mmol) in tetrahydrofuran (30 ml), keeping the temperature below 5° C. The reaction mixture was stirred at room temperature overnight, quenched by addition of water/saturated aqueous ammonium chloride (50 ml/50 ml) and extracted with ethyl acatate (2×100 ml). The organic phases were washed with brine (100 ml), combined, dried (MgSO4) and evaporated to an amber oil (25.55 g). This oil was dissolved in tetrahydrofuran (50 ml), the solution cooled to 0° C. and treated with a solution of tetrabutylammonium fluoride (1.1 M in tetrahydrofuran, 100 ml, 110 mmol). After stirring at room temperature for 20 minutes the solution was concentrated in vacuo, diluted with water (250 ml) and extracted with ethyl acatate (2×100 ml). The extracts were washed with brine (100 ml), combined, dried (MgSO4) and evaporated to give the title product as an oil (18.65 g, 95%); m/z (ES+) 246 ([M+H]+).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])[CH3:9]>C1(C)C(C)=CC=CC=1>[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3])[CH3:9]
Reactant: CCOc1ccccc1O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1C
Product: CCOc1ccccc1OS(=O)(=O)N=C=O
Temperature: 140 °C

Procedure:
67.9 g (0.48 mol) of chlorosulfonyl isocyanate are added dropwise at 25° C. to a solution of 55.2 g (0.4 mol) of 2-ethoxyphenol in 500 ml of xylene. When the dropwise addition is complete, the temperature is increased slowly to 140° C. and the mixture is refluxed for 2.5 hours. The mixture is cooled, and the solvent as well as excess chlorosulfonyl isocyanate are removed on a rotary evaporator. The yellow oil which remains (97.2 g=100% of theory) is employed without further purification.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:43]/[OH:44])/[C:27]([O:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:46]1([C:52]([O:54][CH3:55])=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>C(OCC)(=O)C.CCCCCC>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:43]/[O:44][C:46]2([C:52]([O:54][CH3:55])=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)/[C:27]([O:29][CH:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: COC(=O)C1(Br)CCCCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)C1(O/N=C(\C(=O)OC(c2ccccc2)c2ccccc2)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCCCC1
Yield: 69 %

Procedure:
Benzhydryl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(hydroxyimino)acetate (2.0 g) was treated with methyl 1-bromocyclohexane carboxylate as described in Example 5a to give the title compound (1.7 g, 69%) as a white solid, m.p. 180°-182° C. (ethyl acetate/hexane). [Found: C: 73.73; H: 5.60; N: 5.69. C45H41N3O5S requires C: 73.45; H: 5.62; N: 5.71%] νmax (KBr) 3406, 2945, 1751, and 1528cm-1, δH (CDCl3) 1.36 (5H, m), 1.72 (3H, m), 2.00 (2H, m), 3.69 (3H, s), 6.46 (1H, s), 6.71 (1H, s), 7.15 (1H, s), 7.29 and 7.34 (25H, m).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:8]([C:9]([O:11]CC)=O)=[CH:7][N:6]=[CH:5][N:4]=1.[C:16](=[N:21]O)([NH2:20])[CH:17]([CH3:19])[CH3:18].[O-]CC.[Na+]>C(O)C>[CH:17]([C:16]1[N:21]=[C:9]([C:8]2[C:3]([C:2]([F:1])([F:14])[F:15])=[N:4][CH:5]=[N:6][CH:7]=2)[O:11][N:20]=1)([CH3:19])[CH3:18]
Reactant: CC(C)C(N)=NO
Reactant: CCOC(=O)c1cncnc1C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1noc(-c2cncnc2C(F)(F)F)n1
Temperature: 0 °C

Procedure:
2 g of ethyl 4-trifluoromethylpyrimidine-5-carboxylate and 1.56 g of isobutyramide oxime were initially charged in 15 ml of ethanol and cooled to 0° C. 10 ml of a 1.2 molar sodium ethoxide solution were added dropwise to this solution. The mixture was allowed to warm to room temperature over a period of one hour and then heated under reflux until the reaction, according to TLC, had ended. The reaction mixture was concentrated and the residue was taken up in saturated ammonium chloride solution and extracted with diethyl ether. Chromatographic purification of the crude product gave the desired compound as a yellowish oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([OH:26])[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=3[Cl:25])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34]([C@H:39]([CH3:43])[C:40](O)=[O:41])[CH:33]=[CH:32]2.Cl.C(N=C=NCCCN(C)C)C.O>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([O:26][C:40](=[O:41])[CH:39]([C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([O:28][CH3:27])[CH:30]=4)[CH:35]=3)[CH3:43])[CH2:17][C:18]3[C:19]([Cl:25])=[CH:20][N:21]=[CH:22][C:23]=3[Cl:24])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:14])[F:15])[CH2:3][CH2:2]1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: OC(Cc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cc(C(C)C(=O)OC(Cc3c(Cl)cncc3Cl)c3ccc(OC(F)F)c(OCC4CC4)c3)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
Compound (3) (12.0 g) was dissolved in DMF (100 ml) then (S)-2-(6-methoxy-naphthalen-2-yl)-propionic acid (7.5 g), 4-dimethylaminopyridine (3.6 g), and 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (5.7 g) was added. After stirring at rt for 4 hours, water (1000 ml) is added. The mixture was extracted with EtOAc (500 ml×2), the combined organic layers are dried over sodium sulphate, and the solvent was removed by evaporation under reduced pressure to afford 17.0 g of an oil which is crystallized from EtOH thus obtaining 11.5 g of the title compound as mixture of diastereomers (11) and (13),
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@H:12]([CH3:13])[C@H:11]([OH:14])[C:10]([F:16])([F:15])[C:9]2=[O:17])[CH:5]=[CH:6][CH:7]=1.[I:18]N1C(=O)CCC1=O>C(O)(=O)C.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@H:12]([CH3:13])[C@H:11]([OH:14])[C:10]([F:15])([F:16])[C:9]2=[O:17])[CH:5]=[CH:6][C:7]=1[I:18]
Reactant: O=C1CCC(=O)N1I
Reactant: C[C@H]1[C@H](O)C(F)(F)C(=O)N1c1cccc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: C[C@H]1[C@H](O)C(F)(F)C(=O)N1c1ccc(I)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
To a solution of (4S,5S)-1-(3-chlorophenyl)-3,3-difluoro-4-hydroxy-5-methylpyrrolidin-2-one (110.5 mg) and N-iodosuccinimide (130 mg) in acetic acid (3 mL) was added dropwise conc. sulfuric acid (3 drops), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated, water was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→1/2) to give the title compound as a pale-yellow oil (yield: 113 mg, 69%).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][OH:27])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1.C(OCC)(=O)C>[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][O:27][CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CO)no1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)OCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
A suspension of sodium hydride 60% suspension in mineral oil (18 mg, 0.45 mmol) in anhydrous tetrahydrofuran (1 ml) was cooled to 0° C. and treated with a solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 85) (142 mg, 0.40 mmol) in anhydrous tetrahydrofuran (1 ml) and stirred under a nitrogen atmosphere for 0.5 hours. Ethyl 2-bromopropionate (37 μl, 0.33 mmol) was added and the mixture was stirred for 2 days, being allowed to warm to room temperature over this time. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a gradient system of pentane : ethyl acetate (99:1) to pentane:ethyl acetate (0:100) to afford the title compound as a colourless oil (90 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[C:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[O:21]=[C:19]1[NH:18][C:17](=[O:22])[C:16](=[CH:15][C:12]2[CH:11]=[CH:10][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:1])[C:30](=[O:31])[CH2:29][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:4]=3)=[CH:14][CH:13]=2)[S:20]1
Reactant: CNc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Reactant: O=C(Cl)Cc1ccccc1
Product: CN(C(=O)Cc1ccccc1)c1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1

Procedure:
In a manner similar to that of Example 37(e), by reacting 1 g (3.2 mmol) of 5-(3′-methylaminobiphenyl-4-ylmethylene)thiazolidine-2,4,dione with 470 μl (3.5 mmol) of phenylacetyl chloride, and after purification, 1.4 g (50%) of N-[4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-yl]-N-methyl-2-phenylacetamide are obtained.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]([C:7]1[CH:8]=[C:9]([CH3:29])[C:10]2[O:16][C:15]3[C:17]([Cl:25])=[CH:18][C:19]([NH:21][CH2:22][CH2:23]Cl)=[CH:20][C:14]=3[CH2:13][S:12](=[O:27])(=[O:26])[C:11]=2[CH:28]=1)=[O:6]>CO>[CH3:3][O:4][C:5]([C:7]1[CH:8]=[C:9]([CH3:29])[C:10]2[O:16][C:15]3[C:17]([Cl:25])=[CH:18][C:19]([NH:21][CH2:22][CH2:23][NH:2][CH3:1])=[CH:20][C:14]=3[CH2:13][S:12](=[O:27])(=[O:26])[C:11]=2[CH:28]=1)=[O:6]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Reactant: CN
Solvent: CO
Product: CNCCNc1cc(Cl)c2c(c1)CS(=O)(=O)c1cc(C(=O)OC)cc(C)c1O2
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A 30% methanolic methylamine solution (4 mL) was added to a solution of the carboxylic acid of Example 56k (0.5 g, 1.16 mmol) in methanol, in a pressure reactor vessel under nitrogen atmosphere and kept at 110° C. for 4 h. The reaction mixture was cooled, concentrated partially and the solid that precipitated was filtered, washed with methanol, dried, treated with methanolic HCl solution (10 mL) and stirred at 70° C. for 1.5 h. The reaction mixture was cooled and the solid that precipitated was filtered and washed with methanol to obtain the title compound as an off white solid. Yield: 0.325 g, (65.92%); 1H NMR (DMSO-d6): δ 2.50 (d, 3H, CH3), 2.80 (s, 3H, CH3), 3.10 (t, 2H, CH2), 3.30 (t, 2H, CH2), 3.90 (s, 3H, OCH3), 5.10 (s, 2H, CH2), 6.85-6.90 (m, 2H, Ar), 8.10 (s, 1H, Ar), 8.20 (s, 1H, Ar), 9.0 (t, 1H, NH); MS: m/e (ES+) 425 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CCNCC1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CC(=O)O)cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccc(CC(=O)N3CCCCC3)cc2)=C(C)C1=O
Yield: 31.7 %

Procedure:
4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetic acid (21 mg, 0.063 mmol) obtained in Example 52 and piperidine (0.0094 ml, 0.095 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (7.8 mg, 0.020 mmol, yield 32%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[N:18]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>>[C:27]([O:26][C:24]([N:18]1[CH2:23][CH2:22][N:21]([C:7](=[O:9])[C:6]2[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])[CH2:20][CH2:19]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 96.9 %

Procedure:
A solution of 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2, 1.0 g), tert-butyl 1-piperazinecarboxylate (0.78 g), TBTU (1.4 g) and N-ethyldiisopropylamine (4 mL) was stirred at room temperature for 2 hours. After such time, the reaction mixture was concentrated in vacuo and purified by column chromatography (SiO2) to give 4-(2-Isopropoxy-5-methanesulfonyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester as a colorless foam (1.6 g). The latter was dissolved in dichloromethane (11 mL) and treated with trifluroacetic acid (4.2 mL) for 30 minutes. After such time the reaction mixture was concentrated in vacuo to yield the title compound (1.6 g) as light yellow oil. MS (m/e): 327.1 (M+H+, 100%).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C:7]([O:9][C@@H:10]4[O:16]3)=[O:8])[CH2:4][CH2:3]1.[BH4-].[Na+].C(O)(=O)C>CO>[CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([OH:8])[O:9][C@@H:10]4[O:16]3)[CH2:4][CH2:3]1
Reactant: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@@]4(C)CC[C@@H]1[C@]32OO4
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Reaction time: 1 h

Procedure:
To a solution of 4 g (0.014 m) of qinghaosu (I) in 200 ml of methanol, was added 4 g of sodium borohydride in small portions, keeping the reaction mixture at 0°-5°. After stirring for 60 min, the mixture was neutralized with glacial acetic acid, concentrated and diluted with water. The white precipitate formed was collected and dried. Recrystallization of the solid from acetone-hexane afforded white needles mp: 153°-58° C., 3.2 g (80).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)=[O:17])=[C:11]([OH:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:33](Br)Br.C(O)=O>CN1C(=O)N(C)CC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]([N:15]2[C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]=3[O:30][CH2:33]2)=[O:17])=[CH:20][C:21]=1[C:26]([F:29])([F:27])[F:28]
Reactant: BrCBr
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(OCc2ccccc2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O=CO
Solvent: CN1CCN(C)C1=O
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N1COc2cc(OCc3ccccc3)ccc21
Reaction time: 0.25 h

Procedure:
To a solution of 1.4 g (3.2 mMol) of 1-(4-benzyloxy-2-hydroxy-phenyl)-3-(4-chloro-3-trifluoromethyl-phenyl)-urea in 420 ml DMEU, 700 mg NaH (55% in oil; 16 mMol) are given. After 15 min, 23 ml of CH2Br2 are added and stirring is continued for 6 h. Then 1 ml of formic acid is added and the resulting mixture is evaporated in HV. The residue is dissolved in EtOAc and water. The separated aq. phase is extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; hexane/CH2Cl2 1:1→CH2Cl2) gives the title compound: m.p.: 135-136° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.[CH3:36][C:37]([CH3:42])([CH2:40]O)[CH2:38][OH:39]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:36][C:37]1([CH3:42])[CH2:38][O:39][C:32]2([CH2:31][CH2:30][CH:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:34][CH2:33]2)[O:35][CH2:40]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCC(C)(C)CO3)c2ncnn12
Temperature: 110 °C
Reaction time: 3 h
Yield: 111.4 %

Procedure:
A mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.5 g), 2,2-dimethylpropane-1,3-diol (0.22 g), p-toluenesulfonic acid monohydrate (0.002 g) and toluene (20 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 3 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.66 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[C:4]([C:11]([O:13]CC)=O)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].[NH2:17][C:18]1[N:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=1.BrC1C=CC=CC=1>CCCCCC>[Cl:24][C:21]1[N:20]=[N:19][C:18]([NH:17][C:11]([C:4]2[C:5](=[O:10])[N:6]([CH3:9])[C:7]([CH3:8])=[C:2]([Cl:1])[C:3]=2[OH:16])=[O:13])=[CH:23][CH:22]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: CCOC(=O)c1c(O)c(Cl)c(C)n(C)c1=O
Solvent: Brc1ccccc1
Solvent: CCCCCC
Product: Cc1c(Cl)c(O)c(C(=O)Nc2ccc(Cl)nn2)c(=O)n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
168 mg of ethyl 5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 82 mg of 3-amino-6-chloropyridazine were added to 1.5 ml of bromobenzene, and the mixture was stirred for 4 hours under heat refluxing. The reaction mixture was cooled to room temperature, and n-hexane was added to the reaction mixture. The resulting solid was collected by filtration, washed with a mixture of t-butyl methyl ether and n-hexane, and dried to obtain 180 mg of N-(6-chloro-3-pyridazinyl)-5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereafter, referred to as present compound 17) represented by the formula:
Reaction SMILES: COC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1[CH2:18][S:19](N)(=[O:21])=[O:20].[F:23][C:24]1[CH:25]=[C:26]([CH:64]=[CH:65][CH:66]=1)[CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[C:41]3[C:36](=[N:37][CH:38]=[C:39]([C:42]4[CH:43]=[N:44][C:45]([N:48]5[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]5)=[CH:46][CH:47]=4)[CH:40]=3)[N:35]([S:54]([C:57]3[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=3)(=[O:56])=[O:55])[CH:34]=2)[CH:30]=[N:29]1.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([CH:64]=[CH:65][CH:66]=1)[CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[C:41]3[C:36](=[N:37][CH:38]=[C:39]([C:42]4[CH:43]=[N:44][C:45]([N:48]5[CH2:53][CH2:52][N:51]([S:19]([CH3:18])(=[O:21])=[O:20])[CH2:50][CH2:49]5)=[CH:46][CH:47]=4)[CH:40]=3)[N:35]([S:54]([C:57]3[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=3)(=[O:56])=[O:55])[CH:34]=2)[CH:30]=[N:29]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CS(N)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(S(C)(=O)=O)CC5)nc4)cnc32)cc1
Yield: 100 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 17, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 compound of example 137) (80 mg, 0.13 mmol) was mesylated with methanesulfonyl chloride (23 mg, 0.196 mmol) using triethylamine (40 mg, 0.39 mmol) in DCM (3 mL) to afford 100 mg (100% yield) of the titled compound. MS: m/z=686.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]([CH3:15])[C:7]=1[NH:8][C:9](=[O:14])[CH2:10][O:11][CH2:12][CH3:13].[CH3:17][N:18]=[C:19]=[O:20]>C1(CC#N)C=CC=CC=1.C(N(CC)CC)C>[CH3:17][NH:18][C:19](=[O:20])[O:16][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:14])[CH2:10][O:11][CH2:12][CH3:13])=[C:6]([CH3:15])[CH:5]=1
Reactant: CCOCC(=O)Nc1c(C)cc(O)cc1C
Reactant: CN=C=O
Solvent: N#CCc1ccccc1
Solvent: CCN(CC)CC
Product: CCOCC(=O)Nc1c(C)cc(OC(=O)NC)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3,5-Dimethyl-4-ethoxyacetamidophenol (1.1g., 0.0049 mole, m.p. 157°-59° C., prepared by reaction of ethoxyacetyl chloride with 3,5-dimethyl-4-aminophenol) was reacted with methyl isocyanate (0.3g., 0.0053 mole) using benzeneacetonitrile as solvent and triethylamine as a catalyst. The reaction mixture was stirred at ambient temperature for 31/2 hours, followed by warming at about 45° C. for 2 hours. Solvents were removed under reduced pressure, and the residual solid recrystallized from diethylether and benzene (m.p. 112.5°-115° C.).
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH2:13][Cl:14])([CH3:12])OC(C)C)=[CH:3][CH:2]=1.Br[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.C([Li])CCC>O1CCCC1.CCCCCC>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][C:4]([SiH:7]([CH2:13][Cl:14])[CH2:12][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:5][CH:6]=1
Reactant: CC(C)O[Si](C)(CCl)c1ccc(-c2ccccc2)cc1
Reactant: Fc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Fc1ccc(C[SiH](CCl)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 10.0 g (32.8 mmol) of (1,1'-biphenyl-4-yl)(chloromethyl)methyl(2-propoxy)silane and 3.6 ml (32.8 mmol) of 4-bromofluorobenzene in 30 ml of dry tetrahydrofuran was cooled to -60° under nitrogen and stirred while 20.5 ml (32.8 mmol) of 1.6 molar n-butyllithium in hexane was added at a rate that held the mixture below 50°. After stirring at -70° for another 30 minutes, the solution was allowed to warm to room temperature and was worked up as in Example 8. The resulting crude product was subjected to distillation at 130°-150° (0.2 mm) to remove unreacted starting material, leaving the title compound as an oil: nD23 1.5128; nmr (CDCl3): 0.7 (3H, s), 3.1 (2H, s), 7.1 (2H, t), 7.2-7.8 (11H, m).