Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][B-](F)(F)F.N#[O+].N[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].ClC1C=CC=CC=1Cl>ClCCl>[F:1][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1c([N+](=O)[O-])ccc2ccccc12
Reactant: F[B-](F)(F)F
Agent: N#[O+]
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2ccccc2c1F
Reaction time: 0.5 h

Procedure:
To a well stirred slurry of nitrosonium tetrafluoroborate (Aldrich) (10 % molar excess, (cf. David J. Milner, Synthetic Communications (1992) 22 (1), 73-82.)) in dichloromethane at 0° C. is added 1-amino-2-nitronaphthalene. After 30 minutes, ortho-dichlorobenzene is added and the dichloromethane is distilled off, and the dichlorobenzene is heated at 50°-200 ° C. to decompose the diazonium tetrafluoroborate. Removal of solvent and purification of the product by chromatography or crystallization yields 1-fluoro-2-nitronaphthalene.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:23]=2[CH2:24]Cl)=[CH:18][CH:17]=1>CC(C)=O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:23]=2[CH2:24][O:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(-c2ccc(Cl)cc2)c(CCl)c1
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(-c2ccc(Cl)cc2)c(COc2ccc(I)cc2)c1
Yield: 98.8 %

Procedure:
4-Iodophenol (5.0 g) was dissolved in acetone (50 ml), and potassium carbonate (4.7 g) and 4′-chloro-2-chloromethyl-4-methoxybiphenyl (6.0 g) obtained in Example 241, Step 4 were added. The mixture was refluxed for 10 hr. The reaction mixture was concentrated and 4N aqueous sodium hydroxide solution (50 ml) was added. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give the title compound (10.0 g, yield 98%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[N:3]1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:16][N:17]=[C:18]=[O:19]>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:16][NH:17][C:18]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[N:3][N:2]2[CH3:1])=[O:19]
Reactant: Cn1ncc2c(N)cccc21
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: Cn1ncc2c(NC(=O)NCc3ccc(Cl)c(Cl)c3)cccc21
Temperature: 80 °C

Procedure:
1-Methyl-1H-indazol-4-amine (390 mg, 2.65 mmol) and 3,4-dichlorobenzyl isocyanate (0.39 mL, 2.65 mmol) were combined in toluene (20 mL) and heated overnight at 80° C. The mixture was allowed to cool to ambient temperature, filtered, and the filter cake was allowed to air-dry to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, d6-DMSO) δ 8.86 (s, 1H), 8.06 (d, J=1.0 Hz, 1H), 7.59-7.64 (m, 3H), 7.33 (m, 1H), 7.25 (m, 1H), 7.15 (m, 1H), 6.91 (t, J=6.0 Hz), 4.35 (d, J=5.8 Hz, 2H), 3.99 (s, 3H); MS (ESI+) m/z 349/351 (M+H, 35Cl/37Cl)+.
Reaction SMILES: Cl[C:2]1[N:25]=[C:5]2[C:6]([N:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[CH3:11])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:24][N:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:10]([CH3:11])[C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:39][C:36]3[CH:35]=[CH:34][C:33]([N:30]4[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]4)=[CH:38][CH:37]=3)[N:25]=2)[CH:9]=[CH:8][CH:7]=1)[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CN(Cc1ccccc1N(C)S(C)(=O)=O)c1cccn2nc(Cl)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(N(C)Cc5ccccc5N(C)S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
185 b) N-Methyl-N-{2-[(methyl-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino}-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-amino)-methyl]-phenyl}-methanesulfonamide was prepared from N-(2-{[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-methyl-amino]-methyl}-phenyl)-N-methyl-methanesulfonamide (75.0 mg, 0.197 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (42.0 mg, 0.220 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (18.0 mg, 0.0329 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.023 g, 21%). 7.94 (d, J=6.6 Hz, 1H), 7.56-7.51 (m, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.35-7.28 (m, 3H), 6.88 (d, J=8.1 Hz, 2H), 6.70 (t, J=7.3 Hz, 1H), 6.57-6.50 (m, 2H), 5.35-5.23 (m, 1H), 5.12-5.00 (m, 1H), 3.23 (s, 3H), 3.15-3.10 (m, 4H), 3.07 (s, 3H), 2.99 (s, 3H), 2.63-2.58 (m, 4H), 2.36 (s, 3H). MS=535 (MH)+.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[N:12][C:7]=2[S:6](=[O:15])(=[O:14])[NH:5][CH2:4]1)[CH3:2].[OH-].[Na+].[C:18]1(C)C=CC(S(OC)(=O)=O)=CC=1>C(#N)C>[CH3:18][N:5]1[CH2:4][N:3]([CH2:1][CH3:2])[C:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[N:12][C:7]=2[S:6]1(=[O:14])=[O:15]
Reactant: CCN1CNS(=O)(=O)c2ncc(C)cc21
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCN1CN(C)S(=O)(=O)c2ncc(C)cc21

Procedure:
A solution of 0.2 g of 4-ethyl-6-methyl-2,3- dihydro-4H-pyrido[3,2-e][1,2,4]thiadiazine 1,1-dioxide (Example 79) in 10 cm3 of acetonitrile is treated with 2 equivalents of NaOH and then brought to reflux for 15 minutes with stirring. The mixture is treated with 0.18 g of methyl p-toluenesulfonate and stirred for 2 hours at ambient temperature. The solvent is then removed under reduced pressure and the residue is taken up in 5 cm3 of water. The precipitate is collected on a filter, washed with water and dried. It is purified by chromatography on a silica column (1/1 chloroform/diethyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)[CH:5]=[CH:6][CH:7]=1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[C:22]([Si:19]([CH3:21])([CH3:20])[O:18][CH:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH2:11][CH:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C1CCC(CCC(O)Cc2cccc(Cl)c2)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(Cl)c1
Yield: 81.1 %

Procedure:
Analogous to the procedure described for Example 1A, Step C, 5-[4-(3-chloro-phenyl)-3-hydroxy-butyl]-pyrrolidin-2-one (1.53 g, 5.71 mmol) was reacted with tert-butyldimethylsilyl chloride (0.97 g, 6.4 mmol). Purification by medium pressure chromatography using a solvent gradient (1:1 hexanes:EtOAc to EtOAc to 1% MeOH in CH2Cl2 to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2) provided 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-chloro-phenyl)-butyl]-pyrrolidin-2-one (1.77 g). 1H NMR (CDCl3) δ7.16 (m, 3H), 7.01 (m, 1H), 5.61 (d, 1H), 3.83 (m, 1H), 3.58 (m, 1H), 2.68 (m, 2H), 2.28 (m, 3H), 1.73-1.36 (m, 5H), 0.84 (s, 9H), −0.05 (s, 3H), −0.2 (d, 3H).
Reaction SMILES: [NH2:1][C:2]([CH3:13])([CH3:12])[CH2:3][S:4][C:5]1[N:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1.[CH3:14][O:15][CH2:16][CH2:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[O:20][CH2:21][CH:22]1[O:24][CH2:23]1>CO>[CH3:14][O:15][CH2:16][CH2:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[O:20][CH2:21][CH:22]([OH:24])[CH2:23][NH:1][C:2]([CH3:13])([CH3:12])[CH2:3][S:4][C:5]1[N:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: CC(C)(N)CSc1ccc(Cl)nn1
Reactant: COCCc1ccccc1OCC1CO1
Solvent: CO
Product: COCCc1ccccc1OCC(O)CNC(C)(C)CSc1ccc(Cl)nn1
Yield: 27.9 %

Procedure:
A solution of 980 mg of 3-(2-amino-2-methylpropylthio)-6-chloropyridazine and 960 mg of 1-[2-(2-methoxyethyl)phenoxy]-2,3-epoxypropane in 60 ml of methanol was treated in the same way as in Example 1, (b) to give 534 mg of 1-[2-(2-methoxyethyl)phenoxy]-3-[1,1-dimethyl-2-(3-chloro-6-pyridazinylthio)ethylamino]-2-propanol.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.[C:9]1([C:15](=[N:22][NH2:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCO>[C:15](=[N:22]/[N:23]=[CH:7]/[C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Br:1])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: O=Cc1sccc1Br
Solvent: CCO
Product: Brc1ccsc1/C=N/N=C(c1ccccc1)c1ccccc1
Temperature: 65 °C
Yield: 102 %

Procedure:
To a solution of 3-bromothiophene-2-carbaldehyde (5.57 g, 29.2 mmol) in EtOH (90 mL) was added (diphenylmethylene)hydrazine (6.3 g, 32.1 mmol). The reaction mixture was heated at 65° C. for 4 h then concentrated. The residue was purified by silica gel chromatography with 10% to 20% EtOAc/heptane to afford 11 g of N-benzhydrylidene-N′-[1-(3-bromo-thiophen-2-yl)-meth-(E)-ylidene]-hydrazine as a viscous yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[S:18]([O-:21])([O-:20])=[O:19].[Na+].[Na+].C(O)C>O>[OH:21][S:18]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2)(=[O:20])=[O:19]
Reactant: O=S([O-])[O-]
Reactant: O=c1ccc2cc(OCCCCCl)ccc2[nH]1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1ccc2cc(OCCCCS(=O)(=O)O)ccc2[nH]1
Reaction time: 72 h
Yield: 75.4 %

Procedure:
A solution of 53.3 g of 6-(4-chlorobutoxy)carbostyril and 32 g of sodium sulfite dissolved in 500 ml of water and 200 ml of ethanol was refluxed for 1 day. The solution was allowed to cool and stand for 3 days and then filtered. The filtrate was made acidic with diluted hydrochloric acid. The solvent was removed by distillation. To the resulting residue was-added water, and the precipitate was collected by filtration to obtain 47.5 g of 6-(4-hydroxysulfonylbutoxy)carbostyril as a white powder.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:25](O)=[O:26])=[O:19])([CH3:16])([CH3:15])[CH3:14].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[C:59]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)(=[O:62])[NH:60][NH2:61]>CN(C=O)C>[C:13]([O:17][C:18]([CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:25]([NH:61][NH:60][C:59]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])=[O:26])=[O:19])([CH3:15])([CH3:16])[CH3:14]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(=O)O)cc1OCC(=O)OC(C)(C)C
Reactant: NNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(C(=O)NNC(=O)OCc2ccccc2)cc1OCC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92 g) was added to a mixture of the product of step (c) (3.82 g), HOBT (1.71 g), diisopropylethylamine (1.75 ml) and DMF (30 ml) at ambient temperature and stirred for 30 minutes. Benzyl carbazate (1.66 g) in DMF (10 ml) was added and the mixture was stirred for 20 hours at ambient temperature. The solvent was removed by evaporation. The residue was dissolved in ethyl acetate (160 ml) and the solution was washed with 1M citric acid solution (25 ml), water (2×25 ml), 1M sodium hydroxide solution (20 ml), water (25 ml) and with saturated sodium chloride solution (25 ml) and dried (MgSO4). The solvent was removed by evaporation to give benzyl 3-(3,4-di-t-butoxycarbonylmethoxybenzoyl)carbazate as a gum; NMR Spectrum (d6 -DMSO) 1.43 (s, 18H), 4.70 (s, 2H), 4.75 (s, 2H), 5.11 (s, 2H), 6.96 (d, 1H), 7.34 (br s, 5H), 7.4 (d, 1H), 7.49 (dd, 1H), 9.28 (br s, 1H), 10.17 (br s, 1H); Mass Spectrum (+ve FAB, DMSO/GLYCEROL) 530 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(OC1C=CC=CC=1)=O.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=1[N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1.[N-:30]=[N+:31]=[N-:32].[Na+]>ClCCl.N1C=CC=CC=1>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:30]=[N+:31]=[N-:32])=[O:19])=[CH:16][C:15]=1[N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C(=O)O)cc1N1CCN(C)CC1
Agent: O=P(Cl)(Cl)Oc1ccccc1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)N=[N+]=[N-])cc1N1CCN(C)CC1
Reaction time: 12 h

Procedure:
At ambient temperature, add a solution of 5.3 g (0.025 mol) of phenyl dichlorophosphate in 100 ml of dichloromethane to a solution of 5 g (0.02 mol) of 4-methoxy-3-(4-methyl piperazin-1-yl)benzoic acid [J. Med. Chem., 37 (15), 2255 (1994)] and 3.25 g (0.05 mol) of sodium azide in 4.05 ml of pyridine. After stirring for 12 hours, wash the organic phase with 100 ml of water, separate off the organic phase, dry it over magnesium sulphate and evaporate off the solvent in vacuo at 30° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:11][C:9](=[O:10])[C:8]([CH2:12][C:13]3[C:22](=[O:23])[O:21][C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:14]=3O)=[C:7](O)[C:5]=2[CH:6]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl.C(N(CC)CC)C>[CH2:12]([C:8]1[C:9](=[O:10])[O:11][C:4]2[C:3]([C:7]=1[S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)(=[O:34])=[O:33])=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:13]1[C:22](=[O:23])[O:21][C:20]2[C:15]([C:14]=1[S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)(=[O:34])=[O:33])=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: O=c1oc2ccccc2c(O)c1Cc1c(O)c2ccccc2oc1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)c2c(Cc3c(S(=O)(=O)c4ccc(C)cc4)c4ccccc4oc3=O)c(=O)oc3ccccc23)cc1

Procedure:
To a solution of dicumarol (10 mmol) and p-toluenesulfonyl chloride (1.0 eq.) in dichloromethane (20 ml), triethylamine was added at room temperature under air atmosphere. After the reaction was complete, as monitored by TLC, the reaction mixture was evaporated and the residue was purified by flash chromatography (silica gel) to afford the product, 3,3′-methylenebis[4-tosylcoumarin].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.CO[CH2:16][Cl:17].[Sn](Cl)(Cl)(Cl)Cl.O>ClCCl>[Cl:17][CH2:16][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: COCCl
Reactant: CCOC(=O)c1ccc(OC)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OC)c(CCl)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
Ethyl 4-methoxybenzoate (28.0 mL) and 26.0 mL of methoxymethyl chloride were dissolved in 500 mL of dichloromethane, and the solution was cooled to 0° C. To this solution, 10.0 mL of tin (IV) chloride was added dropwise over 15 minutes, and then the mixture was stirred for 5 hours. The reaction mixture was poured into 1 L of water, and the organic layer was separated, whereafter the aqueous layer was extracted twice with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and washed with dichloromethane. The filtrate and the washings were combined, and dichloromethane was distilled off under reduced pressure. The resulting residue was recrystallized from a mixture of n-hexane and ethyl acetate. The resulting crystals were separated by filtration, then washed with n-hexane, and dried under reduced pressure to obtain 23.8 g (60%) of ethyl 3-chloromethyl-4-methoxybenzoate.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:18]Br>C(O)(=O)C.O>[Br:18][C:9]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:8]=1[NH2:10]
Reactant: BrBr
Reactant: Cc1ccccc1-n1nc(C(C)(C)C)cc1N
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccccc1-n1nc(C(C)(C)C)c(Br)c1N
Reaction time: 0.08 h
Yield: 73.3 %

Procedure:
To a solution of 3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (1.00 g, 4.36 mmol) in acetic acid (10 mL) was added bromine (662 mg, 0.21 mL, 4.14 mmol) dropwise. The reaction mixture was stirred for 5 min, and then diluted with water (50 mL), causing a solid to precipitate. The solid was collected by filtration, then dissolved in EtOAc (50 mL). The EtOAc solution was then washed with saturated NaHCO3 and brine, dried (Na2SO4), and concentrated under reduced pressure to afford the product (935 mg, 70%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 1.32 (s, 9H), 2.04 (s, 3H) 5.02 (s, 2H), 7.20-7.38 (m, 4H). ES-MS m/z 308.6 (MH+); HPLC RT (min) 3.15.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[CH3:12][N:13]([CH3:19])[CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:16]1[CH2:17][CH2:18][CH:14]([N:13]([CH3:19])[CH3:12])[CH2:15]1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CN(C)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C1CCN(c2ccc([N+](=O)[O-])cc2Cl)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-chloro-1-fluoro-4-nitrobenzene (4.79 g), dimethylpyrrolidin-3-ylamine (2.60 g), potassium carbonate (3.82 g) and DMF (35 mL) was stirred at room temperature for 4 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was extracted with hydrochloric acid (2 M), and the extract was basified with sodium hydroxide solution (2M). Extraction with ethyl acetate afforded an organic phase which was dried and concentrated. The product with the molecular weight of 269.73 (C12H16ClN3O2) was obtained in this way; MS (ESI): 270 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([NH:9][C:10]2[O:11][C:12]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)=[N:13][N:14]=2)=[O:8])[S:5][CH:6]=1.[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[C:20]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]([C:7]([NH:9][C:10]3[O:11][C:12]([C:15]4[O:16][CH:17]=[CH:18][CH:19]=4)=[N:13][N:14]=3)=[O:8])[S:5][CH:6]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cc(Br)cs1
Product: O=C(Nc1nnc(-c2ccco2)o1)c1cc(-c2ccc(-c3ccccc3)cc2)cs1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 4-bromo-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-2-thiophenecarboxamide prepared in Reference Example 12 instead of compound Ia-50 and using commercially available 4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[H-].[Na+].F[C:11]1[CH:12]=[CH:13][C:14]2[S:15](=[O:26])(=[O:25])[C:16]3[C:21]([O:22][C:23]=2[CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3.O>CN(C)C(=O)C>[F:1][C:2]([F:7])([F:6])[CH:3]([CH3:4])[O:5][C:11]1[CH:12]=[CH:13][C:14]2[S:15](=[O:25])(=[O:26])[C:16]3[C:21]([O:22][C:23]=2[CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3
Reactant: O=S1(=O)c2ccccc2Oc2cc(F)ccc21
Reactant: CC(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(Oc1ccc2c(c1)Oc1ccccc1S2(=O)=O)C(F)(F)F
Temperature: 12.5 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
(rac)-1,1,1-Trifluoro-2-propanol (Oakwood) (189.30 g, 1.66 mole) in N,N-dimethylacetamide (200 mL) was added to a stirred, ice-bath cooled mixture of hexanes washed sodium hydride (60% dispersion in mineral oil) (Aldrich) (66.40 g, 1.66 mole) and N,N-dimethylacetamide (1900 mL) under nitrogen. The reaction was stirred at ambient temperature (5-20° C.) for 0.5 hour. 3-Fluorophenoxathiin 10,10-dioxide (Example 47) (277.78 g, 1.11 mole) in N,N-dimethylacetamide (1800 mL) was added at a bath temperature of 5-15° C. and stirred at ambient temperature for 1 hour. The reaction mixture was poured into water (8 L) and extracted with ethyl acetate (3 L, 2 L). The combined extracts were washed with water (4 L, 2 L), brine (0.5 L), dried over magnesium sulfate and filter. The volatiles were removed by spin evaporation in vacuo. The residue was stirred with hexanes (1 L) and collected by suction filtration to give 399.51 g of crude product. Recrystallization from 2-propanol (1.5 L) gave 304.62 g (79% yield) of (rac)-3-(2,2,2-trifluoro-1-methylethoxy)phenoxathiin 10,10-dioxide, m.p. 98-100 C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[Cl:11].[CH3:12][C:13]1[N:18]=[C:17]([SH:19])[N:16]=[C:15]([OH:20])[CH:14]=1.C(N(CC)CC)C>C(O)C>[Cl:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[CH2:2][S:19][C:17]1[N:16]=[C:15]([OH:20])[CH:14]=[C:13]([CH3:12])[N:18]=1
Reactant: COc1ccc(CBr)c(Cl)c1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(CSc2nc(C)cc(O)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
A mixture of 1-(bromomethyl)-2-chloro-4-methoxybenzene (1.0 g, 4.2 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (550 mg, 3.9 mmol), and triethylamine (585 μL, 4.2 mmol) in absolute ethanol (20 mL) was stirred at room temperature overnight. The product was recovered by filtration, washed with water (2×20 mL) and diethyl ether (2×20 mL), and dried in vacuo, affording the title compound (929 mg, 81% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.07 (s, 3H), 3.76 (s, 3H), 4.41 (s, 2H), 6.00 (s (br), 1H), 6.89 (dd, 1H, J=2.5 Hz, 8.6 Hz), 7.07 (d, 1H, J=8.6 Hz), 7.52 (d, 1H, J=8.6 Hz); M+ 297.
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH:11][C:12]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)=[O:13])[CH:5]=1>C(O)(=O)C>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH+:11]([O-:1])[C:12]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)=[O:13])[CH:5]=1
Reactant: OO
Reactant: Cc1cc(C)nc(NC(=O)c2cnccn2)c1
Solvent: CC(=O)O
Product: Cc1cc(C)nc([NH+]([O-])C(=O)c2cnccn2)c1
Temperature: 70 °C

Procedure:
A solution of 10 ml of glacial acetic acid and 0.7 ml of aqueous hydrogen peroxide solution (35%) are added, with stirring, to 1 g of compound obtained in Example 21. The reaction medium is heated at 70° C. for 7 h and then concentrated under reduced pressure and at low temperature.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11](Cl)=[O:12])[CH3:2].[N+:14](=[CH2:16])=[N-:15]>C(Cl)Cl.CCOCC>[N+:14](=[CH:16][C:11](=[O:12])[CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])=[N-:15]
Reactant: C=[N+]=[N-]
Reactant: CCc1ccccc1CCC(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCc1ccccc1CCC(=O)C=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
A solution of 3-(2-ethylphenyl)propanoyl chloride (crude, 23.8 mmole) in methylene chloride was slowly added to a solution of diazomethane (generated from 15.6 g of 1-methyl-3-nitro-1-nitrosoguanidine) in ether (100 ml) cooled in an ice bath. The mixture was then warmed up to room temperature and stirred overnight. The mixture was concentrated in vacuo and purified by column chromatography (10→20% ethyl acetate/hexanes) to give 1-diazo-4-(2-ethylphenyl)butan-2-one (3.47 g, 72% over 2 steps). 1H NMR (CDCl3) δ 7.1-7.25 (4H, m, phenyl), 5.21 (1H, broad s, diazo), 2.97 (2H, m, CH2 of ethyl), 1.20 (3H, t, CH3). Step 3: