Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:13][CH2:14][C:15]([OH:17])=O)=[C:8]([Cl:12])[C:9]=2[CH3:11])[S:4][C:3]=1[C:18](=[O:23])[NH:19][CH:20]1[CH2:22][CH2:21]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.[NH2:56][CH2:57][CH2:58][N:59]1[CH2:63][CH2:62][CH2:61][CH2:60]1>CN(C=O)C.C1COCC1>[CH:20]1([NH:19][C:18]([C:3]2[S:4][C:5]3=[N:6][C:7]([O:13][CH2:14][C:15](=[O:17])[NH:56][CH2:57][CH2:58][N:59]4[CH2:63][CH2:62][CH2:61][CH2:60]4)=[C:8]([Cl:12])[C:9]([CH3:11])=[C:10]3[C:2]=2[NH2:1])=[O:23])[CH2:21][CH2:22]1
Reactant: NCCN1CCCC1
Reactant: Cc1c(Cl)c(OCC(=O)O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)c(OCC(=O)NCCN2CCCC2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.1 %

Procedure:
To a solution of (3-amino-5-chloro-2-cyclopropylcarbamoyl-4-methyl-thieno[2,3-b]pyridin-6-yloxy)-acetic acid (0.300 g, 0.843 mmol) in a 1:1 mixture of THF:DMF (2.0 ml each) are added 1-hydroxybenzotriazole hydrate (0.148 g, 1.096 mmol), N,N-diisopropylethylamine (0.163 g, 1.265 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.242 g, 1.265 mmol), and 1-(2-aminoethyl)pyrrolidine (0.289 g, 2.529 mmol). The resulting solution is stirred at room temperature for 16 hours. The reaction is quenched by the addition of water (25 ml). A yellow precipitate formed. The mixture is cooled to 0° C. and stirred for 10 minutes, then filtered. The collected solid is dried in the vacuum oven for 3 hours at 60° C. This affords the title compound as a yellow solid (0.069 g, 18%). Mass (m/z): 452.2 (M++1), 450.2 (M+−1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]#[N:11])=[CH:4][C:3]=1[NH2:12].C(O)CCCC.[CH2:19]([CH:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:26]=O)[CH2:20][CH2:21][CH2:22]CC.O=O>CN1C(=O)CCC1>[C:10]([C:5]1[C:6]([C:8]#[N:9])=[CH:7][C:2]2[N:1]=[C:26]([CH:25]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[NH:12][C:3]=2[CH:4]=1)#[N:11]
Reactant: CCCCCCC(C=O)CCCCCC
Reactant: N#Cc1cc(N)c(N)cc1C#N
Agent: O=O
Solvent: CN1CCCC1=O
Solvent: CCCCCO
Product: CCCCCCC(CCCC)c1nc2cc(C#N)c(C#N)cc2[nH]1
Temperature: 120 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
A 100 mL round-bottom flask was charged with 3 (1.32 g, 8.37 mmol), pentanol (42 mL), 2-hexyl-1-octanal (1.77 g, 8.37 mmol), and a magnetic stirring bar. The flask was fitted with a Hickman still and placed in an oil bath heated to 120° C. NMP (4.0 mL) was added to fully dissolve the solid material. The mixture was heated and stirred for 2 h. Then FeCl3.6H2O (113 mg, 0.42 mmol) was added to the reaction vessel and oxygen was bubbled through the mixture as it was heated and stirred for an additional 12 h. The reaction mixture was then removed from heat and added to 200 mL diethyl ether. The ether solution was washed three times with water, then washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was chromatographed (silica, CHCl3), yielding a tan solid (2.37 g, 81%): 1H NMR δ 0.82 (t, J=7.6 Hz, 6H), 1.10-1.30 (m, 16H), 1.77-1.87 (m, 2H), 2.90-3.04 (m, 1H), 8.07 (br s, 2H), 10.36 (br s, 1H); 13C NMR δ 14.2, 22.8, 27.7, 29.4, 31.8, 34.9, 41.3, 108.4, 117.0, 165.3; FAB-MS obsd 351.2551, calcd 351.2549 (C22H30N4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[C:8]1=[O:27].[CH2:35]([O:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[NH:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:36]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:52][CH2:51][CH:50]([NH:49][C:41]3[N:40]([CH2:39][CH2:38][O:37][CH2:35][CH3:36])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)[CH2:55][CH2:54]2)([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[C:8]1=[O:27]
Reactant: COc1cc(CN2CCC(CCOS(C)(=O)=O)(Cc3cccc(F)c3)C2=O)cc(OC)c1OC
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Product: CCOCCn1c(NC2CCN(CCC3(Cc4cccc(F)c4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzyl)-3-(3-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:3][C:4]=2[CH:10]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc2nc(N3CCNCC3)sc2c1

Procedure:
A mixture of 10 mmol 2,6-dichlorobenzothiazole, 12.3 mmol of piperazine and 20 mmol of potassium carbonate in 50 ml of acetonitrile was refluxed for 3 hours. The reaction mixture was concentrated and treated with 25 ml of water. Extraction with ethyl acetate, drying over magnesium sulfate, and evaporation of the solvent yielded the title compound as a colorless solid.
Reaction SMILES: CS[C:3]([S:16][CH3:17])=[CH:4][C:5]([CH:7]1[CH:15]2[CH:8]1[CH2:9][C:10]1([CH2:14]2)[CH2:13][O:12][CH2:11]1)=[O:6].[F:18][CH:19]([F:37])[O:20][C:21]1[C:22]([NH2:36])=[N:23][CH:24]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>S1C=CC=C1C([O-])=O.[Cu+].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.O1CCCC1.O>[NH2:36][C:22]1[N:23]=[CH:24][C:25](/[C:3](/[S:16][CH3:17])=[CH:4]\[C:5]([CH:7]2[CH:15]3[CH:8]2[CH2:9][C:10]2([CH2:14]3)[CH2:13][O:12][CH2:11]2)=[O:6])=[CH:26][C:21]=1[O:20][CH:19]([F:37])[F:18]
Reactant: CC1(C)OB(c2cnc(N)c(OC(F)F)c2)OC1(C)C
Reactant: CSC(=CC(=O)C1C2CC3(COC3)CC21)SC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu+]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CS/C(=C/C(=O)C1C2CC3(COC3)CC21)c1cnc(N)c(OC(F)F)c1
Temperature: 110 °C
Yield: 18.8 %

Procedure:
To a solution of 3,3-bis(methylthio)-1-(spiro[bicyclo[3.1.0]hexane-3,3′-oxetan]-6-yl)prop-2-en-1-one (250 mg, 924 mmol) in 6:1 tetrahydrofuran/water (3.5 mL) was added 3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (317 mg, 1.11 mmol), copper(I) thiophene-2-carboxylate (353 mg, 1.85 mmol), cesium carbonate (602 mg, 1.85 mmol), and bis(triphenylphosphine)palladium(II) dichloride (65 mg, 92 mmol). The reaction mixture was heated at 110° C. with microwave irradiation for 1.5 h. The reaction mixture was concentrated, and the resulting residue was purified by flash column chromatography (ethyl acetate) to afford product as a white solid (0.080 g, 23%).
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[Br:9][C:10]1[CH:11]=[C:12]([C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][C:15]=1[F:16]>O1CCCC1>[Br:9][C:10]1[CH:11]=[C:12]([C:17](=[O:19])[CH2:18][C:3]([O:6][CH3:7])=[O:8])[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: CC(=O)c1ccc(F)c(Br)c1
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)c1ccc(F)c(Br)c1

Procedure:
To a suspension of sodium hydride (1.1 g of 60% suspension in mineral oil, hexane-washed, 27.6 mmol) in 50 mL of tetrahydrofuran was added dimethyl carbonate (2.3 mL, 27.6 mmol) and 3′-bromo-4′-fluoroacetophenone (3.0 g, 13.8 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1CC1OC(N)=NC=1.ClC(CC1C=CC=CC=1OC)C=O.[NH2:29]C(N)=O>C(O)C>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[NH2:29]
Reactant: NC(N)=O
Reactant: COc1ccccc1Cc1cnc(N)o1
Agent: COc1ccccc1CC(Cl)C=O
Solvent: CCO
Product: COc1ccccc1N

Procedure:
5-(2-methoxy-benzyl)-oxazol-2-ylamine. A mixture of 2-chloro-3-(2-methoxylphenyl)-propionaldehyde (10 g, crude from above) and urea (9.6 g, 0.16 mol) was dissolved in ethanol (250 mL) and then heated to reflux overnight. The solvent was evaporated to dryness. The residue was diluted with dichloromethane (250 mL) and then washed with sodium hydroxide (10% aqueous solution, 100 mL) and water (50 mL). The organic layer was extracted three times with hydrochloric acid (5% aqueous solution, 250 mL). The combined aqueous layers were adjusted to pH 9 to 10 with a 10% aqueous solution of sodium hydroxide and then extracted three times with dichloromethane (300 mL). The organic layer was separated, dried over sodium sulfate, and evaporated to dryness. The crude product was purified by silica gel column chromatography to yield the yellow-red solid product, (0.72 g, 0.35% from 2-methoxyaniline). ESI-MS m/z calc. 204.1, found 205.1 (M+1)+ 1H NMR(CDCl3) δ 7.26-7.20 (m, 1H), 7.14 (d, J=7.2 Hz, 1H), 6.91-6.86 (m, 2H), 6.35 (s, 1H), 4.49 (bs, 2H), 3.85 (s, 2H), 3.82 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:11][O:10]2)=[CH:5][N:4]=1.[N-:12]=[N+:13]=[N-:14].[Na+].Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[N:12]([C@@H:9]([C:6]1[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:11][OH:10])=[N+:13]=[N-:14]
Reactant: COc1ccc([C@@H]2CO2)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: COc1ccc([C@@H](CO)N=[N+]=[N-])cn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 68.7 %

Procedure:
To a stirred solution of (R)-2-methoxy-5-(oxiran-2-yl)pyridine (1.02 g, 6.75 mmol) in acetonitrile (100 mL) were added sodium azide (1.8 g, 27 mmol) and lithium perchlorate (11 g, 0.10 mol) and the mixture was stirred at 60° C. for 4 h. TLC indicated completion of the reaction. After cooling, the mixture was filtered through Celite and the filtrate was concentrated. The residue was treated with water and extracted with EtOAc (3×50 mL). The combined organic layers were washed with aq. NaHCO3 and brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel column (0-50% EtOAc/hexane) to yield a light yellow oil (0.9 g, 69%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1.[H-].[Na+].Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[C:15]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1)([CH3:22])[CH3:21])[CH3:20]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: OB1OCc2ccc(O)cc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)B(O)OC2
Temperature: 0 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
H181 (150 mg, 1.0 mmol) was dissolved in DMF (7.0 mL) and cooled to 0° C. with ice bath. To this solution under nitrogen were added in sequence NaH (60% in mineral oil, 160 mg, 4.0 mmol) and ethyl 2-bromo-2-methylpropanoate (0.59 mL, 4.0 mmol). The reaction mixture was stirred for 1 d then treated with 1.0 M HCl (10.0 mL). After extraction with ethyl acetate, the organic phase was washed with water and brine, and dried over anhydrous Na2SO4. The residue after rotary evaporation was purified by column chromatography over silica gel to give the title compound (161 mg, 61% yield). 1H NMR (300 MHz, CDCl3): δ 7.23 (d, J=8.1 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 7.04 (dd, J=8.4 & 2.7 Hz, 1H), 5.04 (s, 2H), 4.25 (q, J=6.9 Hz, 2H), 1.60 (s, 6H) and 1.26 (t, J=7.2 Hz, 3H) ppm; Mp: 63-66° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[N:5]([CH3:7])[CH3:6].[CH3:11][CH:12]([OH:16])[CH2:13][CH:14]=[CH2:15].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>C(N(CC)CC)C.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:6][N:5]([CH3:7])[C:4]1[CH:3]=[C:2](/[CH:15]=[CH:14]/[CH2:13][CH:12]([OH:16])[CH3:11])[CH:10]=[CH:9][CH:8]=1
Reactant: C=CCC(C)O
Reactant: CN(C)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(O)C/C=C/c1cccc(N(C)C)c1
Yield: 63.7 %

Procedure:
A mixture of 3-bromo-N,N-dimethylaniline (1.00 g, 5.00 mmol), 4-penten-2-ol (450 mg, 5.23 mmol), palladium(II) acetate (11 mg, 0.050 mmol) and tri-o-tolylphosphine (61 mg, 0.20 mmol) was diluted with triethylamine (1.5 mL) and acetonitrile (3 mL) and refluxed under nitrogen for 16 h. The mixture was cooled, poured into water (15 mL) and extracted with chloroform (2×15 mL). The chloroform extracts were dried (Na2SO4) and evaporated. The residue was column chromatographed on 35 g of Merck silica gel 60 (70-230 mesh) with 10-20% (v/v) ethyl acetate, 20% (v/v) chloroform in hexane to give 657 mg (63.7% yield) of light yellow oil.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:13].[OH-].[Na+]>N1C=CC=CC=1>[NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[S:13]
Reactant: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=c1[nH]c(=S)[nH]c2nc[nH]c12
Yield: 322.7 %

Procedure:
2.77 g (8.0 mM) of xanthine and 2.13 g (9.6 mM) of phosphorus pentasulfide were heated under reflux in 50 ml of pyridine for 7 days. At 0° C., 10.6 ml of 2N NaOH were added within 15 min. The solvents were evaporated in vacuo and the residue suspended (slow crystallization) in water. The solid was collected and washed, redissolved in 50 ml of 1N NaOH and 50 ml of isopropanol, treated twice with 0.3 g of charcoal, filtered neutralized with 5N HCl to pH 7. The isopropanol was distilled off with addition of water and the solid collected, washed and dried to give 2.60 g (89.7%) of crude thioxanthine, which was dissolved in 40 ml of dichloromethane and filtered through 30 g of silica gel: 1.91 g (65.9%) of 6-thioxanthine were recovered, mp 153-4° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11]2([CH3:20])[CH3:19])[CH:8]=[N:7][CH:6]=1)=[O:4].S(=O)(=O)(O)[OH:22].[NH4+].[NH4+].[O-]S(OOS([O-])(=O)=O)(=O)=O.[OH-].[Na+]>O>[CH3:1][O:2][C:3]([C:5]1[N:9]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]2([CH3:20])[CH3:19])[CH:8]=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cncn1C1c2ccccc2CC1(C)C
Reactant: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cncn1C1c2ccccc2C(=O)C1(C)C
Yield: 60.2 %

Procedure:
A mixture of 30.0 g of 1-(2,2-dimethylindan-1-yl)-5-imidazolecarboxylic acid methyl ester, 150 ml of water and 17 g of sulfuric acid is heated to +80° C. Within a period of 1.5 hours a solution of 114 g of ammonium peroxodisulfate is added dropwise thereto. When the reaction is complete, the solution is cooled to +7° C. and adjusted to pH 3 by the addition of 30% sodium hydroxide solution. The solution is extracted twice using 200 ml of methylene chloride each time, and the organic phase is dried over sodium sulfate and concentrated to dryness by evaporation. The residue is taken up in a small amount of methylene chloride, and ether is added. The resulting suspension is filtered, the filtrate is concentrated by evaporation and the residue is crystallised from an ether/hexane mixture. 19 g of 1-(2,2-dimethyl-3-oxoindan-1-yl)-5-imidazolecarboxylic acid methyl ester having a melting point of 104°-108° C. are obtained.
Reaction SMILES: ClC1C(C)=CC(F)=C(C=1)C(OC(C)(C)C)=O.C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:43][C:44]1[C:45]([CH:58](Br)[Br:59])=[CH:46][C:47]([F:57])=[C:48]([CH:56]=1)[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:43][C:44]1[C:45]([CH2:58][Br:59])=[CH:46][C:47]([F:57])=[C:48]([CH:56]=1)[C:49]([O:51][C:52]([CH3:54])([CH3:55])[CH3:53])=[O:50]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(C(Br)Br)cc1F
Agent: Cc1cc(F)c(C(=O)OC(C)(C)C)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1cc(Cl)c(CBr)cc1F
Temperature: 85 °C
Reaction time: 18 h

Procedure:
To a stirred solution of tert-butyl 5-chloro-2-fluoro-4-methylbenzoate (Preparation 24, 4.60 g, 18.8 mmol) in carbon tetrachloride (60 mL) was added NBS (3.70 g, 20.7 mmol) and dibenzoyl peroxide (228 mg, 0.94 mmol). The resulting mixture was stirred under nitrogen at 85° C. for 18 hours. Additional NBS (7.60 g, 41.4 mmol) was added and the mixture stirred for 4 hours. Further NBS (1.00 g, 5.6 mmol) and dibenzoyl peroxide (200 mg, 0.85 mmol) were then added and the reaction mixture was left to stir under nitrogen at 85° C. for 18 hours. The reaction mixture was then cooled to room temperature and diluted with CH2Cl2 (50 mL). The organic layer was washed with water (50 mL), aqueous sodium thiosulfate solution (50 mL), dried over MgSO4, and concentrated under vacuum to give the crude product as a yellow oil. The crude product was purified by column chromatography on silica (eluent 95:5 heptane/EtOAc) yielding a 2:1 mixture of the title compound (tert-butyl 5-chloro-4-(bromomethyl)-2-fluorobenzoate) and tert-butyl 5-chloro-4-(dibromomethyl)-2-fluorobenzoate (3.96 g). To a stirred solution of the mixture of tert-butyl 5-chloro-4-(bromomethyl)-2-fluorobenzoate and tert-butyl 5-chloro-4-(dibromomethyl)-2-fluorobenzoate in EtOAc (25 mL) were added N,N-diisopropylethylamine (2.60 mL, 14.8 mmol) and diethyl phosphate (1.30 ml, 9.80 mmol) dropwise. The reaction mixture was stirred under nitrogen at room temperature for 18 hours. The reaction mixture was washed with aqueous solution of 1M HCl (30 mL) and brine (30 mL), dried over MgSO4 and concentrated under vacuum to give the crude product as an orange oil. This was purified by column chromatography on silica (eluent 9:1 heptane/EtOAc) yielding the title compound as an orange oil (2.9 g, 48%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:17]1([N:10]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:16]3[C:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:7][CH:6]=3)=[N:9]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Oc1ccc(-c2nn(-c3ccccc3)c3ncccc23)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(-c2nn(-c3ccccc3)c3ncccc23)cc1

Procedure:
4-(1-Phenyl-1H-pyrazolo[3,4-b]pyridin-3-yl)phenoxyacetic acid can be produced by reacting 3-(4-hydroxyphenyl)-1-phenyl1H-pyrazolo[3,4-b]pyridine with ethyl bromoacetate in the presence of potassium carbonate as a deacidifying agent in dimethylformamide to obtain ethyl 4-(1-phenyl-1H-pyrazolo[3,4-b]pyridin-3-yl)phenoxyacetate, followed by hydrolysis thereof with the use of sodium hydroxide.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3](=[O:17])[CH:4]([CH3:16])[CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]C)[CH:9]=1)[CH2:6][CH3:7].I>>[CH3:18][N:2]([CH3:1])[C:3](=[O:17])[CH:4]([CH3:16])[CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[CH2:6][CH3:7]
Reactant: CCC(c1cccc(OC)c1)C(C)C(=O)N(C)C
Agent: I
Product: CCC(c1cccc(O)c1)C(C)C(=O)N(C)C
Temperature: 25 °C

Procedure:
The steps are: add compound 7 into a reaction flask, add hydroiodic acid, perform heating and reflux for 5 hours; detect the reaction process by TLC; after that, cool the resultant to the room temperature, pour it to an alkaline solution to make the pH become 9, and perform extraction by ethyl acetate and rinse by water; and recycle the solvent after drying and decompression to obtain a light yellow liquid, N,N-dimethyl-2-methyl-3-(3-hydroxyphenyl) valeramide (compound 9).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[NH:9][S:10](=[O:20])(=[O:19])[C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1>CO>[Cl:18][C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:8]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[NH:9][S:10](=[O:20])(=[O:19])[C:11]=2[CH:17]=1
Reactant: O=S1(=O)NC(Cl)=Nc2ccc(Cl)cc21
Reactant: C1CNCCN1
Solvent: CO
Product: O=S1(=O)NC(N2CCNCC2)=Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
To a stirred solution of 3.4 g of anhydrous piperazine in 25 ml of methanol is added 5.0 g of 3,7-dichloro-2H-1,2,4-benzothiadiazine 1,1-dioxide, while the mixture is cooled in an ice bath. After the addition, the mixture is stirred at room temperature for 3 hours. The crystalline precipitate is collected by suction filtration and treated with a mixture of 2 ml of concentrated hydrochloric acid and 40 ml of water. After removal of the insoluble materials by suction filtration, the filtrate is adjusted to a pH 8.0 with a dilute aqueous sodium hydroxide solution to give 3.9 g of the desired product, m.p. 292°-295° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:22][O:23][CH:24]([O:41][CH3:42])[C:25]1[C:30]([O:31][CH2:32][O:33][CH3:34])=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:28]=[CH:27][C:26]=1[CH2:39]O>>[CH3:42][O:41][CH:24]([O:23][CH3:22])[C:25]1[C:30]([O:31][CH2:32][O:33][CH3:34])=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:28]=[CH:27][C:26]=1[CH2:39][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])=[CH:11][CH:10]=2)=[CH:3][C:2]=1[F:1]
Reactant: C=CCOC(=O)Cc1ccc(-c2ccc(O)c(F)c2)cc1
Reactant: COCOc1c(C(F)(F)F)ccc(CO)c1C(OC)OC
Product: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCOC)c3C(OC)OC)c(F)c2)cc1
Yield: 93 %

Procedure:
According to a method similar to Example (6-7), from allyl (3′-fluoro-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (300 mg, 1.05 mmol) obtained in Example (12-2) and [2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)phenyl]methanol (500 mg, 1.61 mmol) obtained in Example (6-6), allyl (4′-{[2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl]oxy}-3′-fluoro-1,1′-biphenyl-4-yl)acetate was obtained (618 mg, yield: 93%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CN(C)CCN(C)C.[CH3:21][Si:22]([CH3:32])([CH3:31])[O:23][C:24]([CH3:30])=[CH:25][C:26]([O:28][CH3:29])=[O:27].[CH3:33][Si:34](Cl)([CH3:36])[CH3:35]>C1COCC1>[CH3:29][O:28][C:26]([O:27][Si:34]([CH3:36])([CH3:35])[CH3:33])=[CH:25][C:24]([O:23][Si:22]([CH3:31])([CH3:21])[CH3:32])=[CH2:30]
Reactant: COC(=O)C=C(C)O[Si](C)(C)C
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=C(C=C(OC)O[Si](C)(C)C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To diisopropylamine (6.8 ml, 48 mm) in THF at 0° C. is added 30 ml of 1.6 M n-butyllithium (48 mm), then 6.5 ml tetramethylethylenediamine (TMEDA, 48 mm) cooled to -78° C. Then 7.6 g (40 mm) of methyl 3-trimethylsilyloxybut-2-enoate is added over 5 minutes at -70° C. The mixture is stirred at -75° for 10 minutes, then 8 ml (48 mm) trimethylsilylchloride is added over 5 minutes at -75° C. The solution is warmed to room temperature and concentrated in vacuo. The residue is slurried in 500 ml of n-hexane, and solids filtered off. The filtrate is concentrated in vacuo, B.P.=75°-76° C. at 0.3 mm Hg.