Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[CH3:9][O:10][C:11]1[C:12]([CH3:38])=[C:13]([C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[NH:28][CH:27]=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:25]3=[O:37])=[O:21])[N:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]2>CN(C=O)C>[CH3:9][O:10][C:11]1[C:12]([CH3:38])=[C:13]([C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]([CH3:1])[CH:27]=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:25]3=[O:37])=[O:21])[N:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c2ccc(C(=O)c3c(C)c(OC)c4ccccn34)cc2c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2ccc(C(=O)c3c(C)c(OC)c4ccccn34)cc2c1=O
Temperature: 90 °C
Yield: 93.6 %

Procedure:
3.8 g (27.89 mmol) of potassium carbonate and 1.74 ml (27.89 mmol) of methyl iodide are added, at ambient temperature under an inert atmosphere, to 10 g (23.24 mmol) of ethyl 6-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate in 100 ml of DMF. The reaction medium is heated at 90° C. for 1 h 30. The reaction medium is filtered through talc, diluted with dichloromethane, and then washed with water. The organic phase is dried with sodium sulphate and then concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (90/10) mixture. 9.1 g of a yellow solid are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>C(C(C)=O)C>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:26](=[O:27])[CH2:25][CH2:24][Cl:23])=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)CCCl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CCCl)Oc1ccc(C(=O)c2ccccc2)cc1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
6.7 g (35 mmol) of 4-hydroxy-benzophenone was dissolved in 100 ml methyl ethyl ketone. 4.2 g (42 mmol) triethyl amine was added and the mixture was cooled to −10° C. 5.3 g (42 mmol) 3-chloro-propionyl chloride was added drop wise, while the temperature was kept below −5° C. The reaction was allowed to continue for 30 minutes at 0° C. and 3 hours at room temperature. The precipitated salts were removed by filtration and the solvent was evaporated under reduced pressure. 3-Chloro-propionic acid 4-benzoylphenyl ester was isolated by preparative column chromatography on a Prochrom LC80 column, using n-hexane/ethylacetate 75/25 as eluent at a flow rate of 150 ml/min and Kromasil 60A 10 micron as silica. 1.2 g of 3-chloro-propionic acid 4-benzoylphenyl ester was isolated.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:35]=[C:34]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:33]=[CH:32][C:6]=1[O:7][CH2:8][CH:9]([OH:31])[CH2:10][O:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:4].[CH2:50](Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C)C=O>[CH2:3]([C:5]1[CH:35]=[C:34]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:33]=[CH:32][C:6]=1[O:7][CH2:8][CH:9]([O:31][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:10][O:11][C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH3:4]
Reactant: CCCCCCCCCCCCCCc1ccc(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCc1ccc(OCC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)OCc2ccccc2)c(CC)c1
Reaction time: 0.25 h
Yield: 98.2 %

Procedure:
To a suspension of 2.016 g of prewashed sodium hydride in 125 ml of dimethylformamide was added dropwise a solution of 17.75 g of 1-(2-ethyl-4-tetradecylphenoxy)-3-(triphenylmethoxy)-2-propanol in 125 ml of dimethylformamide. This mixture was stirred 15 minutes, then 7.198 g of benzyl bromide was added and stirring was continued for an additional 3 hours. The reaction mixture was quenched slowly with water and then extracted several times with ether. The ether extracts were combined, washed with water, dried and the solvent evaporated, giving 19.9 g of the desired compound.
Reaction SMILES: [CH3:1][NH:2][S:3]([NH:6][C:7]([N:9]1[CH2:12][C@H:11]([NH:13]C(OCC2C=CC=CC=2)=O)[C:10]1=[O:24])=[O:8])(=[O:5])=[O:4].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[H][H].N1CCC1=O>C(#N)C.[Pd]>[NH2:13][C@H:11]1[CH2:12][N:9]([C:7]([NH:6][S:3]([NH:2][CH3:1])(=[O:5])=[O:4])=[O:8])[C:10]1=[O:24]
Reactant: [H][H]
Reactant: CNS(=O)(=O)NC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=C1CCN1
Solvent: CC#N
Product: CNS(=O)(=O)NC(=O)N1C[C@H](N)C1=O
Reaction time: 0.5 h

Procedure:
(S)-N-[(Methylamino)sulfonyl]-2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinecarboxamide (2.1 g; see Example 37) was suspended in 25 ml of acetonitrile and bis(trimethylsilyl)acetamide (3.3 g) was added. The solution was added to a suspension of 1 g of 10% palladium on charcoal in 25 ml of acetonitrile, through which hydrogen was passed for 30 minutes prior to the addition of the solution of the starting azetidinone. After 15 minutes the catalyst was removed by filtration and 2 ml of methanol was added to the filtrate to precipitate 1.3 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH2:10])=[N:6][CH:7]=1.N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:17](=[O:19])[CH3:18])=[N:6][CH:7]=1
Reactant: NCCc1ccc(Br)cn1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCCc1ccc(Br)cn1
Temperature: 25 °C

Procedure:
A mixture of 200 mg (1.00 mmol) 2-(5-bromopyridin-2-yl)ethanamine, 86.6 μL (1.09 mmol) pyridine and 2 mL DCM is charged with 103 μL (1.09 mmol) acetic anhydride and stirred at r.t. over night. The mixture is treated with saturated aq. NaHCO3 solution and extracted with DCM. The organic layer is dried with Na2SO4 and the solvent is evaporated in vacuo.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.C(#N)C>[C:6]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[C:14]([OH:16])=[O:15])([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Yield: 85 %

Procedure:
N-Boc-L-pipecolic acid (0.280 g, 1.22 mmol) was esterified with 1-phenyl-7-(3'-pyridyl)-heptan-4-ol (0.394 g, 1.46 mmol) employing EDC hydrochloride (0.350 g, 1.83 mmol) and 4-dimethylaminopyridine (0.081 g, 0.663 mmol) in acetonitrile (25 mL). Purification by silica gel chromatography, eluting with chloroform/methanol (100:0 to 99:1), gave the pure 1-phenyl-7-(3'-pyridyl)-heptan-4-ol ester of N-Boc-pipecolic acid in 85% yield (0.498 g) as a colorless oil. MS: M+H=481. LC-MS: System 2 (4 min gradient), tR =3.8 min. A portion of this N-Boc ester (0.369 g, 0.768 mmol) was deprotected as described in example 1 with trifluoroacetic acid. The crude product was then coupled with α,α-difluoro-3,4,5-trimethoxyphenylacetic acid (0.241 g, 0.921 mmol), using EDC hydrochloride (0.220 g, 1.15 mmol) and 4-dimethylaminopyridine (0.101 g, 0.826 mmol) in acetonitrile (25 mL). After extractive work up as described in example 1, the product was purified by silica gel chromatography, eluting with hexane/ethyl acetate (4:1 to 1:1), to give the title compound (0.624 g, 1.05 mmol, 78%) as a pale yellow oil. MS: M+H=625. 1H-NMR: 8.38-8.34 (m, 2H), 7.75-7.00 (m, 7H), 6.76-6.63 (m & s, 2H), 5.25-4.10 (4×m, 2H), 3.80-3.50 (m, 1OH), 3.00-2.85 (m, 1H), 2.52 (m, 2H), 2.25-1.00 (4×m, 16H). LC-MS: System 2 (4 min gradient), tR, for the diastereomers=3.6 and 3.8 min. Anal. C35H42N2O6F2, C=67.40, H=6.85, N=4.23, F=5.86 (found) C=67.29, H=6.78, N=4.48, F=6.08 (calcd.).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:35][CH3:36])[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([CH:33]=[O:34])[C:21]4[S:25][C:24]([NH:26][C:27](=[O:31])[NH:28][CH2:29][CH3:30])=[N:23][C:22]=4[CH:32]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[K+]>C1COCC1.O>[CH2:35]([C:6]1([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([C:12]2[N:13]=[CH:14][C:15]([C:18]3[CH:19]=[C:20]([CH:33]=[O:34])[C:21]4[S:25][C:24]([NH:26][C:27](=[O:31])[NH:28][CH2:29][CH3:30])=[N:23][C:22]=4[CH:32]=3)=[CH:16][N:17]=2)[CH2:8][CH2:7]1)[CH3:36]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)OCC)CC4)nc3)cc(C=O)c2s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)O)CC4)nc3)cc(C=O)c2s1
Yield: 63.4 %

Procedure:
Ethyl-4-ethyl-1-[5-[2-(ethylcarbamoylamino)-7-formyl-1,3-benzothiazol-5-yl]pyrimidin-2-yl]piperidine-4-carboxylate (1.75 g, 3.43 mmol) was dissolved in THF (60 mL) and MeOH (125 mL) and an aqueous solution of KOH (125 mL; 1 mol/L) was introduced and refluxed overnight. After this period the mixture was diluted with water (150 mL), washed with Et2O/EtOAc (1:1, 100 mL) and the residual aqueous acidified to pH 1 (3M HCl) and back extracted with EtOAc (3×100 mL). The organic fractions were combined, dried (MgSO4) and concentrated in vacuo affording 1.05 g (64% yield) of the product as a light yellow solid after flash column chromatography on silica gel (0-10% DCM/MeOH). 1HNMR (CDCl3): δ 10.16 (s, 1H), 8.56 (d, J=20.7 Hz, 2H), 7.95 (d, J=1.5 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 4.51 (d, J=13.9 Hz, 2H), 3.39-3.32 (m, 2H), 3.26-3.15 (m, 2H), 2.20 (d, J=13.4 Hz, 2H), 1.59 (q, J=7.5 Hz, 2H), 1.48-1.34 (m, 2H), 1.21 (t, J=7.2 Hz, 3H), 0.87 (t, J=7.5 Hz, 3H). MS: 483.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9]2=[N:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[N:17][N:8]2[C:7]1=[O:24])[CH2:2][CH2:3][CH2:4][CH3:5].C(N1C2N=CNC=2C2=NN=C(C3C=CN=CN=3)N2C1=O)CCCC.[Br:49]N1C(=O)CCC1=O>C1COCC1>[Br:49][C:12]1[NH:11][C:10]2[C:9]3=[N:15][C:16]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][N:19]=4)=[N:17][N:8]3[C:7](=[O:24])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: CCCCCn1c(=O)n2nc(-c3ccncn3)nc2c2[nH]cnc21
Reactant: O=C1CCC(=O)N1Br
Agent: CCCCCn1c(=O)n2c(-c3ccncn3)nnc2c2[nH]cnc21
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n2nc(-c3ccncn3)nc2c2[nH]c(Br)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-pentyl-8-pyrimidin-4-yl-1,4-dihydro-5H-[1,2,4]triazolo[5,1-i]purin-5-one (14C1) and 6-pentyl-3-pyrimidin-4-yl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purin-5-one (14C2) (25 mg, 0.15 mmol) in THF (5 mL) was added N-bromosuccinimide (19 mg, 0.22 mmol). The reaction mixture was stirred at room temperature for 1 hour, then the reaction was quenched by phenol. After removing the solvent, the residue was purified using preparative LCMS (method B) to yield the pure compound (14D1) and the pure compound 14D2 respectively. LCMS calculated for C15H16BrN8O (M+H): 403.1. found: 403.0, 405.0.
Reaction SMILES: N[C:2]1[S:6][C:5]2[CH2:7][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ICI.N(OCCC(C)C)=O.[BH4-].[Na+]>C(O)C.C(OCC)(=O)C.O1CCCC1>[OH:23][CH:16]([C:3]1[C:4]2[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][C:5]=2[S:6][CH:2]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)C1CCc2c(sc(N)c2C(=O)c2ccccc2)C1
Agent: CC(C)CCON=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ICI
Solvent: CCO
Product: CCOC(=O)C1CCc2c(C(O)c3ccccc3)csc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
A mixture of 21.5 g of 2-amino-3-benzoyl-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene, 12.5 g of cuprous iodide, 26.3 ml of diiodomethane, 26.3 ml of isopentyl nitrite and 250 ml of tetrahydrofuran was heated under reflux for 1.5 hours. After cooling as it was, 500 ml of ethyl acetate was added to the reaction solution. The insoluble matters were filtered off, the mixture was subjected to silica gel column chromatography, and eluted with hexane and then with hexane/ethyl acetate (10:1), to give 17.4 g of a crude product. 1.5 g of sodium borohydride was added little by little to a solution of 200 ml of ethanol containing 17.4 g of this crude product under ice-cooling. After stirring at room temperature for one hour, the solvent was removed. Ethyl acetate and water were added to the residue, followed by extracting with ethyl acetate. The organic phase was washed with brine and the solvent was removed. The residue was subjected to silica gel column chromatography, and eluted with hexane and then with hexane/ethyl acetate (4:1), to give 11.2 g of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[CH3:13][Mg+].[Br-]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([OH:12])([CH3:13])[CH3:11]
Reactant: C[Mg+]
Reactant: COc1ccc(C(C)=O)c(F)c1
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)O)c(F)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 2′-fluoro-4′-methoxyacetophenone (4.45 g, 26.5 mmol) in THF (50 ml) at 0° C., a solution of 2.4 M MeMgBr (11.6 mmol, 27.8 mmol) was added. The mixture was stirred at 0° C. and then room temperature for 4 h. The reaction was quenched with saturated ammonium chloride solution. The organic was extracted with ethyl acetate (3×50 ml). The combined ethyl acetate layers were washed with brine and dried over sodium sulfate. The resulting alcohol was obtained as an oil after flash column using EtOAc:hexane=2:8 as the elute.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[O:13][C:14]([CH2:17][CH2:18][CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:16]=1)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:25][CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17][C:14]1[O:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:26])=[O:3])=[CH:16][CH:15]=1
Reactant: CCCCCC(O)CCc1ccc(CCCCCCCC(=O)OCC)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCCC(O)CCc1ccc(CCCCCCCC(=O)O)o1

Procedure:
A mixture of VI (2.73 g, 0.00745 mole), methanol (100 ml), and 20% aqueous potassium carbonate solution (30 ml) was stirred and heated under reflux for 1 hour. The turbid solution was concentrated to 1/4 of the volume by distillation from a water bath (60°C) under reduced pressure (60 mm Hg). The residue was diluted with water (100 ml) and adjusted to pH 7 with acetic acid (2.7 ml). The resulting emulsion was extracted with two 80-ml portions of ether. The combined ethereal extracts were washed with water (100 ml) and then dried over magnesium sulfate. Ether was distilled off from a water bath (50°C), at last under 15 mm Hg. The yellow, oily residue (2.58 g) was purified by crystallization from petroleum ether (boiling below 50°C) (450 ml). 2.13 g (84%) of VIa were hereby obtained as almost white crystals with m.p. 43°-45°C.
Reaction SMILES: [Li].[Cl:2][C:3]1[CH:4]=[C:5]([C:10]([O-])=[CH:11][C:12](=O)[C:13]([O:15]CC)=[O:14])[CH:6]=[N:7][C:8]=1[F:9].ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:43][C:44]1[CH:45]=[C:46]([NH:50][NH2:51])[CH:47]=[CH:48][CH:49]=1>>[Cl:43][C:44]1[CH:45]=[C:46]([N:50]2[C:10]([C:5]3[CH:6]=[N:7][C:8]([F:9])=[C:3]([Cl:2])[CH:4]=3)=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[N:51]2)[CH:47]=[CH:48][CH:49]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cnc(F)c(Cl)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cnc(F)c(Cl)c2)n(-c2cccc(Cl)c2)n1

Procedure:
240 mg (0.86 mmol) of the compound of Example 15A is reacted analogously to the synthesis of the compound of Example 20A with 230 mg (1.29 mmol) of 3-chlorophenylhydrazine hydrochloride. After hydrolysis, 21 mg (7% of theory) of the title compound is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([OH:21])[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1>>[CH3:9][C:4]1[N:5]=[C:6]([NH:10][C:11]2[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[C:13]([OH:21])[CH:12]=2)[CH:7]=[C:2]([NH:10][C:11]2[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[C:13]([OH:21])[CH:12]=2)[N:3]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: Nc1cc(O)cc(C(F)(F)F)c1
Product: Cc1nc(Nc2cc(O)cc(C(F)(F)F)c2)cc(Nc2cc(O)cc(C(F)(F)F)c2)n1
Yield: 43 %

Procedure:
This compound was obtained (yield 43%) based on the method described in Production Example 2B using 4,6-dichloro-2-methylpyrimidine instead of the 4,6-dichloro-2-ethylpyrimidine, and using 3-amino-5-trifluoromethyl-phenol instead of the 3-aminophenol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[C:14](O)(=[O:18])[C:15]([CH3:17])=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O>C(Cl)(Cl)Cl.O>[CH3:17][C:15](=[CH2:16])[C:14]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:18]
Reactant: C=C(C)C(=O)O
Reactant: O=C(O)c1ccc(OCCO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=C(C)C(=O)OCCOc1ccc(C(=O)O)cc1

Procedure:
50 g of p-(2-hydroxyethoxy)-benzoic acid, 130 g of methacrylic acid, 5 g of p-toluenesulfonic acid and 5 g of hydroquinone as an inhibitor are dissolved in 200 ml of CHCl3 and the solution is refluxed in a 500 ml flask, fitted with a water separator and reflux condenser, until about 6 ml of water have separated out (about 20 hours). The cooled solution is introduced into about 1 liter of ether and is washed with 5 portions of water each of about 200 ml. After drying the solution with Na2SO4, the solvents are stripped off and the crude product is recrystallized as described under 1.1.1.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11](O)=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl.P(Br)(Br)[Br:22].C([O-])(O)=O.[Na+]>C1COCC1.CCOCC>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][Br:22])[CH:7]=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: BrP(Br)Br
Reactant: CC(C)(C)C1CCC(C(=O)O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)C1C=CC(CBr)CC1
Temperature: -70 °C
Yield: 31.7 %

Procedure:
4-tert-butylcyclohexancarboxilic acid (2.76 g, 0.015 mol), cis/trans mixture 1:1, in anhydrous THF (10 cm3) was added dropwise to a stirred suspension of LiAlH4 (1.14 g, 0.030 mol) in anhydrous THF (10 cm3), under atmosphere of nitrogen. After 2 h at room temperature the solution was thinned with ether and, under stirring, HCl (10% b.w.) was slowly added dropwise till acidic pH. The two layer were separated and the organic one was washed, then added with Na2SO4 and thoroughly dried under reduced pressure. The residue (2.5 g) was dissolved in anhydrous ether (10 cm3), cooled to -70° C., to which was added dropwise and with stirring PBr3 (1.5 g, 0.055 mol). After the addition was complete the mixture was stirred under reflux to room temperature for 2 h; ether was added and then some satured NaHCO3 solution. After the two layers were separated, Na2SO4 was added to the organic phase which was then dried under reduced pressure. Chromatography on silica gel eluting with hexane gave 1.1 g of 4-tert-butyl-cyclohex-2-enylmethyl bromide (trans isomer) out of 2.4 g of residue. Such product was employed in the example 4.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)=[O:4].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40]Br>C1COCC1>[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40][N:2]([CH3:1])[C:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)=[O:4]
Reactant: CNC(=O)c1ccc(N2CCN(C)CC2)cc1-c1ccccc1C
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ccc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 30.3 %

Procedure:
To a solution of 50 mg (0.15 mmol) 2′-methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid methylamide in 2 ml THF 0.2 ml of a 1 M solution (0.2 mmol) of potassium hexamethyldisilazide in THF was added at 0°. After 20 min. 0.028 ml (0.15 mmol) 3,5-bis(trifluoromethyl)benzyl bromide was added dropwise to the resulting suspension. The reaction was quenched with water after 1.5 h. The mixture was diluted with 5 ml 2 N NaOH solution and extracted with 3 5-ml portions of ethyl acetate. The combined organic extracts were dried (Na2SO4) and evaporated. Chromatography (SiO2, CH2Cl2/methanol 19:1) gave 25 mg (29%) 2′-Methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, MS (ISP): 550.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.[CH:12](O)([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:12]([CH3:14])[CH3:13])=[C:4]([Cl:11])[N:3]=1
Reactant: CC(C)O
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)n1cnc2c(Cl)nc(Cl)nc21

Procedure:
A 500 mL round bottom flask was charged with 2,6-dichloro-9H-purine (1.89 g, 10 mmol), isopropanol (3.1 mL, 40 mmol, 4 mol eq), THF (150 mL), and triphenylphosphine (polystyrene-bound, ˜3 mmol/g, 6.7 g, or about 20 mmol load) and the resulting mixture was stirred and cooled in a water bath under nitrogen. A solution of DBAD (4.85 g, 20 mmol) in THF (50 mL) was added dropwise via an addition funnel over 30 min and the resulting reaction mixture stirred at ambient temperature for 20 hr. The resin was removed by filtration and washed well with ethyl acetate. The combined filtrates were evaporated to give a light yellow solid that was purified via flash column chromatography (dry loaded using silica/DCM) with a gradient of 0-50% ethyl acetate in heptanes to give:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[CH:24][C:25]([C:27](O)=[O:28])=[CH:26][C:17]=4[C:16]=3[N:30]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH2:39])=[CH:33][CH:32]=1>>[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH:39][C:27]([C:25]2[CH:24]=[CH:23][C:18]3[NH:19][C:20](=[O:22])[CH2:21][C:15]4[CH:14]=[N:13][C:12]([NH:11][C:5]5[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)=[N:30][C:16]=4[C:17]=3[CH:26]=2)=[O:28])=[CH:33][CH:32]=1
Reactant: COc1ccc(Nc2ncc3c(n2)-c2cc(C(=O)O)ccc2NC(=O)C3)cc1OC
Reactant: NCCc1ccncc1
Product: COc1ccc(Nc2ncc3c(n2)-c2cc(C(=O)NCCc4ccncc4)ccc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described for Method N, 2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylic acid (I-43) and 2-(pyridin-4-yl)ethanamine were converted I-48 (6%): HRMS Calcd. for C28H26N6O4: 551.2093, Found 511.2098.