Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](=[O:5])[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][C:16]=1[OH:20]
Reactant: COc1cccc(OC)c1
Reactant: O=C(Cl)c1cc(F)ccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2cc(F)ccc2F)c(O)c1
Reaction time: 0.5 h

Procedure:
To a mixture of 30 g of 2,5-difluorobenzoyl chloride and 23.5 g of 1,3-dimethoxybenzene in 300 ml 1,2-dichloroethane, 23 g of aluminum chloride is added in portions with the internal temperature maintained at approximately 8°-12° C. The reaction mixture is stirred 0.5 hr and refluxed one hr. The reaction mixture is poured into concentrated hydrochloric acid and ice. The organic layer is separated, washed, dried over anhydrous sodium sulfate and evaporated. Trituration of the crude residue gives 2',5'-difluoro-2-hydroxy-4-methoxybenzophenone, mp 109° C. followed by recrystallization from toluene.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][NH:11][C:10](=[O:13])[N:9]1[CH3:14])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:14][N:9]1[C@@H:8]([C:6]([OH:7])=[O:5])[CH2:12][NH:11][C:10]1=[O:13]
Reactant: CN1C(=O)NC[C@@H]1C(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)NC[C@@H]1C(=O)O
Reaction time: 3 h
Yield: 76.9 %

Procedure:
To a solution of (R)-3-methyl-2-oxoimidazolidine-4-carboxylic acid tert-butyl ester (94 mg) in chloroform (2 ml) was added trifluoroacetic acid (1 ml) at room temperature, and the mixture was stirred for 3 hours. This reaction solution was concentrated under reduced pressure, additional toluene (3 ml) was added thereto, and the mixture was again concentrated. To the resulting residue was added diethyl ether (0.5 ml) at room temperature, and the mixture was stirred. Next, n-hexane (2 ml) was added thereto, and the mixture was further stirred. The insoluble substance was collected by filtration, and dried under reduced pressure to give the titled compound (52 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]=1[CH3:24])=[O:5])[CH3:2].C(OC(=O)C(CC(C1C=CC([F:42])=CC=1)=O)C(=O)C)C.FC1C=CC(N)=CC=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:8]([C:18]2[CH:23]=[CH:22][C:21]([F:42])=[CH:20][CH:19]=2)[C:7]=1[CH3:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)n(-c2ccccc2)c1C
Reactant: CCOC(=O)C(CC(=O)c1ccc(F)cc1)C(C)=O
Agent: Nc1ccc(F)cc1
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)n(-c2ccc(F)cc2)c1C

Procedure:
Prepared in analogy to that of 5-(4-fluoro-phenyl)-2-methyl-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester from 2-[2-(4-fluoro-phenyl)-2-oxo-ethyl]-3-oxo-butyric acid ethyl ester and 4-fluoroaniline. The title compound, ESI MS (m/z): 342 (M+H+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34]([N:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)=[O:35])[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: O=C(NCC1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: CCOC(=O)N1CCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (pyrrolidin-3-ylmethyl)-amide (example A146) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1(/[C:4](/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:5]\[CH:6]=[CH:7]\[C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([O:9][C:8](=[O:10])/[CH:7]=[CH:6]/[CH:5]=[C:4](\[CH:1]2[CH2:3][CH2:2]2)/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: COc1ccc(/C(=C/C=C/C(=O)O)C2CC2)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
As in Example 115, (E,E)-5-cyclopropyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid (2.7 g) and 4-nitrophenol (1.844 g) in 20 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (2.3 g) and the mixture was stirred at room temperature overnight. After the usual work up, the ester was crystallized from 2-propanol to yield 2.8 g of (E,E)-5-cyclopropyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester. mp 111°-112.5° C.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([NH2:28])[CH:26]=2)[CH:21]=[N:20]1>>[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:2]3[CH:17]=[C:6]4[C:7]5[C:12]([CH2:13][CH2:14][N:5]4[C:4](=[O:18])[N:3]=3)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=5)[CH:26]=2)[CH:21]=[N:20]1
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: Nc1ccc2cn[nH]c2c1
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2ccc3cn[nH]c3c2)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 1H-indazol-6-ylamine as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 12.95 (br, 1H), 9.76 (s, 1H), 8.60 (s, 1H), 7.96 (s, 1H), 7.72-7.60 (2H), 7.15-6.95 (3H), 6.42 (s, 1H), 4.01 (t, 2H), 3.85 (s, 3H) and 2.98 (t, 2H); MS (ESI) (M+H)+ 360.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12.C(N(CC)C(C)C)(C)C.[CH:36](O)=[O:37]>C(Cl)Cl>[NH2:20][C:16]1[C:15]2[N:14]([C:13]([CH:21]3[CH2:26][CH2:25][N:24]([CH:36]=[O:37])[CH2:23][CH2:22]3)=[N:12][C:11]=2[C:3]2[NH:2][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=[CH:18][N:17]=1
Reactant: Nc1nccn2c(C3CCNCC3)nc(-c3cc4ccccc4[nH]3)c12
Reactant: O=CO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccn2c(C3CCN(C=O)CC3)nc(-c3cc4ccccc4[nH]3)c12
Reaction time: 8 h
Yield: 432.5 %

Procedure:
To a solution of 1-(1H-indol-2-yl)-3-piperidin-4-ylimidazo[1,5-a]pyrazin-8-amine hydrochloride (30.00 mg, 0.0068 mmol) in DCM (0.5 mL, 0.008 mol) was added N-(3-dimethylaminopropyl)-N-ethylcarbodihnide hydrochloride (0.0195 g, 0.102 mmol), N,N-diisopropylethylamine (0.047 mL), 1-hydroxbenzotriaxole hydrate (0.0104 g, 0.0679 mmol) and formic acid (4.7 mg, 0.10 mmol). The reaction was stirred at it overnight then diluted with DCM, washed with saturated NaHCO3 (2×25 mL) and brine (2×25), then dried over Na2SO4 and concentrated in vacuo. The material thus isolated was crystallized from EtOAc to afford 10.6 mg of desired product. 1H NMR (400 MHz, CDCl3): δ 2.04-2.12 (m, 4H), 2.99-3.00 (m, 1H), 3.27-3.32 (m, 2H), 3.85 (m, 1H), 4.49 (m, 1H), 5.70 (br, 2H), 6.80 (s, 1H), 7.13-7.24 (m, 4H), 7.45 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 8.10 (s, 1H), 8.97 (br, 1H). MS (ES+): m/z 361.16 [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH:17](Br)[C:16]2=[O:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:22]#[N:23].[Na+].[I-].[Na+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH:17]([C:22]#[N:23])[C:16]2=[O:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(Br)CCN1c1ccc(OCc2ccccc2)cc1
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1CCN(c2ccc(OCc3ccccc3)cc2)C1=O
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 13 %

Procedure:
300 mg (0.87 mmol) of (RS)-1-(4-benzyloxy-phenyl)-3-bromo-pyrrolidin-2-one is dissolved in 5 ml N,N-dimethylformamide. 64 mg (1.3 mmol) sodium cyanide and 13 mg (0.09 mmol) sodium iodide are added and the suspension stirred for 10 min. at 120° C. The reaction mixture is treated with water and extracted with ethyl acetate to yield 33 mg (13%) of a colorless solid. MS: m/e=293.3 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[O:8]2)[CH2:4][CH2:3]1.[C:17]1([C:23]2[N:24]=[CH:25][C:26]([NH:29][C:30](=O)[O:31]C3C=CC=CC=3)=[N:27][CH:28]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:16]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2([CH2:6][CH2:7][N:2]([C:30]([NH:29][C:26]3[CH:25]=[N:24][C:23]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:28][N:27]=3)=[O:31])[CH2:3][CH2:4]2)[O:8]1
Reactant: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1OC2(CCN(C(=O)Nc3cnc(-c4ccccc4)cn3)CC2)c2ccccc21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of spiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (6.24 g, 26.6 mmol), phenyl N-(5-phenyl-2-pyrazinyl)carbamate (7.59 g, 26.0 mmol) and triethylamine (18 mL, 180 mmol) in chloroform (200 mL) was stirred at 80° C. for 3 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate (100 mL). After the organic layer was washed with 10% citric acid aqueous solution (100 mL), 1N aqueous sodium hydroxide (100 mL) and then saturated saline solution (100 mL), the organic layer was dried over anhydrous Na2SO4 and then concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=½) to provide the subject compound as a colorless solid. The solid was washed with diethyl ether (30 mL) to provide the subject compound (8.23 g) as a crude crystal. The crystal was dissolved in hot ethyl acetate (300 mL). After removal of about 100 mL of ethyl acetate by distillation, the white suspension began to occur. At this point the distillation was stopped and the whole was cooled and then kept at room temperature for 14 hours. The colorless prisms formed was collected by filtration, which was washed with heptane (20 mL). The obtained crystal was dried at 50° C. in vacuo for 6 hours to provide the subject compound (Crystal Form A) (5.17 g) as colorless prisms (melting point 210-211° C.).
Reaction SMILES: [C:1]([NH:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:22][C:23]1([CH3:39])[O:28][CH:27]([C:29]([NH:31][CH2:32][CH2:33][C:34](O)=[O:35])=[O:30])[C:26]([CH3:38])([CH3:37])[CH2:25][O:24]1>>[C:1]([NH:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:34](=[O:35])[CH2:33][CH2:32][NH:31][C:29]([CH:27]2[C:26]([CH3:37])([CH3:38])[CH2:25][O:24][C:23]([CH3:39])([CH3:22])[O:28]2)=[O:30])=[CH:17][CH:16]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)Nc1ccc(N)cc1
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Product: CCCCCCCCCCCC(=O)Nc1ccc(NC(=O)CCNC(=O)C2OC(C)(C)OCC2(C)C)cc1
Yield: 83.3 %

Procedure:
4-Lauroylaminoaniline (250 mg) and 223 mg of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 1 to obtain 381 mg of the title compound (yield: 72%).
Reaction SMILES: Br[CH:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[CH:8][CH:9]=2)[O:4][CH2:3]1.BrC1(Br)C(=O)C2C(=CC(O[Si](C(C)C)(C(C)C)C(C)C)=CC=2)OC1.[OH:48][C:49]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(N(CC)CC)C>C(O)C>[OH:48][C:49]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:54][CH2:53][N:52]([CH:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][C:7]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[CH:8][CH:9]=3)[O:4][CH2:3]2)[CH2:51][CH2:50]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CC(C)[Si](Oc1ccc2c(c1)OCC(Br)C2=O)(C(C)C)C(C)C
Agent: CC(C)[Si](Oc1ccc2c(c1)OCC(Br)(Br)C2=O)(C(C)C)C(C)C
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)[Si](Oc1ccc2c(c1)OCC(N1CCC(O)(c3ccccc3)CC1)C2=O)(C(C)C)C(C)C
Yield: 3 %

Procedure:
7-(Triisopropylsilyloxy)-4-chromanone (2.0 g, 6.2 mmol) was dissolved in CCl4 (45 ml). Bromine (0.3 ml, 6.4 mmol) in CCl4 (5 ml) was added dropwise at ambient temperature over 10 minutes. The reaction initially turned dark red but after stirring for 10 minutes the color changed to light yellow. This yellow solution was washed with dilute NaHSO3, saturated NaHCO3 and brine, dried by filtering through phase separatory paper, and concentrated to yield a brown oil (2.3 g, 93%) which NMR showed was a 2.5:1:1 mixture of 3-bromo-7-(triisopropylsilyloxy)-4-chromanone, 3,3-dibromo-7-(triisopropylsilyloxy)-4-chromanone and starting material. This crude mixture (2.3 g, 5.6 mmol) was combined with 4-hydroxy-4-phenyl piperidine (1.0 g, 5.8 mmol), triethylamine (0.9 ml, 6.5 mmol) and ethanol (50 ml). The reaction was refluxed for 3 hours, then cooled and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over CaSO4, concentrated and the residue chromatographed on silica gel using gradient elution with ethyl acetate/hexanes to give 80 mg (3%) of present title product as a yellow solid, mp 132°-132.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:27]=[O:28].O>O1CCCC1>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH:27]=[O:28])[C:12]=1[F:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)cc1F)OCc1ccccc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1c(F)ccc(NC(=O)OCc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Into a round bottom flask was added (2,4-difluoro-phenyl)-carbamic acid benzyl ester (21, 3.83 g, 14.5 mmol) in 148 mL of tetrahydrofuran. The solution was chilled to −78° C. and n-butyllithium (19.1 mL, 1.60 M in hexane, 30.0 mmol) was added over 30 minutes, followed by the addition of N,N-dimethylformamide (1.12 mL, 14.5 mol). The reaction mixture was allowed to warm to ambient temperature and was stirred overnight, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was crystallized from ether to provide the desired compound (22, 3.0 g, 71%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[C:5]([O:12][C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:16]=[CH:15][N:14]=2)[C:4]([CH3:27])=[N:3]1.[CH:28](OC)=[O:29].[H-].[Na+].C(O)(=O)C>CN(C)C=O>[CH3:11][O:10][C:8](=[O:9])/[C:7](/[C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:27])[C:5]=1[O:12][C:13]1[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[N:16]=[CH:15][N:14]=1)=[CH:28]/[OH:29]
Reactant: COC=O
Reactant: COC(=O)Cc1c(Oc2cc(Oc3ccccc3F)ncn2)c(C)nn1C
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)/C(=C/O)c1c(Oc2cc(Oc3ccccc3F)ncn2)c(C)nn1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.5 g (9.3 mmol) of methyl {1,3-dimethyl-4-[6-(2-fluorophenoxy)pyrimidin-4-yloxy]pyrazol-5-yl}acetate and 10 ml of methyl formate in 10 ml of dimethyl formamide is slowly added dropwise to a suspension of 0.5 g (20.0 mmol) of sodium hydride (95%) in 40 ml of dimethyl formamide, while keeping the temperature below 30° C. The reaction mixture is stirred for 2 hours at room temperature, acidified with acetic acid and, after addition of 200 ml of ice-water, extracted with 200 ml of ethyl acetate. The organic phase is washed with water and sodium chloride solution, dried and concentrated under vacuum, giving E-methyl-2-{1,3-dimethyl-4-[6-(2-fluorophenoxy)pyrimidin-4-yloxy]pyrazol-5-yl}-3-hydroxyacrylate as a brown resin, which is stirred together with 1.8 g (13.0 mmol) of potassium carbonate and 0.9 ml (6.7 mmol) of dimethyl sulfate in 40 ml of acetone for 3 hours at room temperature. The reaction mixture is filtered, the filtrate is diluted with 50 ml of water and extracted with 100 ml of ethyl acetate. The organic phase is washed with sodium chloride solution, dried and concentrated under vacuum. The residue is chromatographed over silica gel tetrahydrofuran/n-hexane (1:1) as eluant, giving E-methyl-2-{1,3-dimethyl-4-[6-(2-fluorophenoxy)pyrimidin-4-yloxy]pyrazol-5-yl}-3-methoxyacrylate as a yellow resin; MS: 414 (M+, 44%), 75 (100).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:13]([O:15]CC)=O)[C:7]2[CH:12]=[N:11][NH:10][C:8]=2[N:9]=1.[NH2:18][CH2:19][C:20]1[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=1[CH3:26]>CCO.CS(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([C:13]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:15])[C:7]2[CH:12]=[N:11][NH:10][C:8]=2[N:9]=1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCOC(=O)c1cc(Br)nc2[nH]ncc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3[nH]ncc23)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
Aqueous NaOH (1.11 g, 27.88 mmol) was added to a solution of ethyl 6-bromo-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (5 g, 18.58 mmol) in EtOH (50 mL) and stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and it was acidified using 10% citric acid solution. Solid obtained was filtered and dried under reduced pressure to obtain corresponding acid. The crude acid (4.4 g, 18.2 mmol) was then dissolved in DMSO (20 mL) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (5.55 g, 36.51 mmol) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYB OP (14.24 g, 27.38 mmol) was added to it and stifling was continued overnight. After completion of the reaction, reaction mass was poured into ice to obtain a solid, which was filtered and washed with acetonitrile followed by ether to provide the desired intermediate (4 g, 58.5%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][O:32]1
Reactant: C1=COCCC1
Reactant: OCCCCCCCCCCCCBr
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: BrCCCCCCCCCCCCOC1CCCCO1
Reaction time: 24 h

Procedure:
To a solution of 12-bromo-1-dodecanol (1 mole) in dichloromethane containing pyridinium p-toluenesulfonate (P-TSA) is added dihydropyran (2 moles). The reaction mixture is stirred for 24 hours and then washed twice with water and dried over anhydrous MgSO4. The dichloromethane is removed under reduced pressure. If necessary the resulting product is purified by chromatography on silica gel.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[Br:9][CH2:10][C:11](Cl)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Br:9][CH2:10][C:11]([C:2]1[CH:3]=[C:4]([CH3:7])[CH:5]=[CH:6][C:1]=1[CH3:8])=[O:12]
Reactant: Cc1ccc(C)cc1
Reactant: O=C(Cl)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(C)c(C(=O)CBr)c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 105.1 %

Procedure:
A mixture of 10.60 g (0.10 mol) of para-xylene and 16.53 g (0.105 mol) of α-bromoacetyl chloride in 300 mL of 1,2dichloroethane was cooled in an ice bath under an atmosphere of dry N2 and treated portionwise with 14.15 g (0.106 mol) of aluminum chloride. The reaction mixture was stirred for 30 minutes at 0-5° C. and then for 2.5 hours at room temperature. The mixture was then poured onto ice and the aqueous layer was acidified with concentrated HCL. The organic layer was separated and the aqueous layer was extracted twice with methylene dichloride. The combined organic extracts were dried with brine solution and with magnesium sulfate. The solvent was evaporated to give 23.87 g of an amber oil which was for use in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]([C@H:20]([C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[CH2:21][C:22]([OH:24])=[O:23])[CH3:19])=[O:17])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2>CCO.C(O)(=O)C.O=[Pt]=O>[NH2:1][C:2]1[N:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]([C@H:20]([C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[CH2:21][C:22]([OH:24])=[O:23])[CH3:19])=[O:17])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: COc1ccc([C@H](CC(=O)O)N(C)C(=O)CCCCc2nc(N)cc3ccccc23)cn1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc([C@H](CC(=O)O)N(C)C(=O)CCCCc2nc(N)cc3c2CCCC3)cn1
Reaction time: 16 h

Procedure:
A solution of the acid 3-5 (150 mg, 0.34 mmol) in EtOH (30 mL) and acetic acid (4 mL) was degassed with argon. PtO2 (25 mg) was added and the mixture placed under an atmosphere of hydrogen gas (balloon) for 16 hours. The mixture was filtered through celite, the solvent removed and the residue purified by reverse phase HPLC (preppak C-18 column; water/acetonitrile/0.1% TFA gradient). After lyophilization, the title compound 3-6 was obtained as a light yellow powder.
Reaction SMILES: [Br-].[C:2]([CH2:4]CC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].C([N-]C(C)C)(C)C.[Li+].CCCCCCC.[O:41]=[C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44](=[O:51])[N:43]1[CH2:52][C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[N:59]=[C:58]([CH2:63][CH2:64][C:65]#N)[CH:57]=[CH:56]2>C1COCC1>[O:51]=[C:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:42](=[O:41])[N:43]1[CH2:52][C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[N:59]=[C:58]([CH:63]=[CH:64][CH2:65][CH2:4][C:2]#[N:3])[CH:57]=[CH:56]2
Reactant: N#CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#CCCc1ccc2cc(CN3C(=O)c4ccccc4C3=O)ccc2n1
Agent: CC(C)[N-]C(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: N#CCCC=Cc1ccc2cc(CN3C(=O)c4ccccc4C3=O)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
The compound (675.0 mg) obtained in Example 123-1 was suspended in anhydrous THF (30 ml) and cooled with ice. Then, the suspension was added with a 2 mol/l lithium diisopropylamide/heptane solution (0.825 ml), followed by stirring at room temperature for 1 hour. Then, the solution was gradually added with a solution prepared by suspending the compound (327.9 mg) obtained in Example 119-7 in anhydrous THF (20 ml), followed by stirring at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (268.0 mg) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][CH2:11][C:12](OCC)(OCC)OCC.O>C(O)C>[Cl:10][CH2:11][C:12]1[O:9][C:3]2[CH:4]=[CH:5][C:6]([Br:8])=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: CCOC(CCl)(OCC)OCC
Solvent: O
Solvent: CCO
Product: ClCc1nc2cc(Br)ccc2o1
Temperature: 25 °C

Procedure:
2-Amino-4-bromophenol (1.6 g) prepared according to U.S. Pat. No. 4,157,444 was dissolved in ethanol (5 ml) and 2-chloro-1,1,1-triethoxyethane (1.9 g) was added. The resulting solution was warmed on a steambath for 1.5 hour. After cooling the reaction mixture to room temperature, cold water (5 ml) was added. The precipitated solid was collected and air-dried to obtain the product (1.12 g; m.p. 63°-65° C.