Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=O.[CH3:3][NH:4][CH2:5][CH2:6][OH:7].[CH3:8][C:9]1[CH:10]=[C:11]([OH:18])[CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2>CCO.C(Cl)Cl>[OH:7][CH2:6][CH2:5][N:4]([CH2:1][C:12]1[C:11]([OH:18])=[CH:10][C:9]([CH3:8])=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2)[CH3:3]
Reactant: Cc1cc(O)cc2cc[nH]c12
Reactant: CNCCO
Reactant: C=O
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(O)c(CN(C)CCO)c2cc[nH]c12
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 77.2 %

Procedure:
A mixture of paraformaldehyde (82.0 mg, 2.71 mmol) and 2-methylaminoethanol (0.218 mL, 2.71 mmol) in EtOH (2 mL) was heated at 50° C. for 20 minutes. 7-methyl-1H-indol-5-ol (Intermediate 11, 500 mg, 3.4 mmol) in EtOH (10 mL) was added and the mixture was stirred for 1.5 hours at room temperature. The mixture was diluted with DCM (15 mL) and divided in two portions to be purified on two SCX-columns (5 g) preconditioned with DCM/MeOH 1:1 (20 mL) and eluted with DCM/MeOH 1:1 (50 mL) (contains only sm) and 1 M MeOH (40 mL) (contains product) to give 490 mg of a brown oil that turned solid. MS m/z 235 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:13]1[C:21]2[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:10][CH2:11][OH:12].ClCCl.ClC1C=CC=C(C(OO)=[O:36])C=1>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:13]1[C:21]2[C:16](=[C:17]([CH2:22][S:23]([CH3:24])=[O:36])[CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:10][CH2:11][OH:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
75.9 mg (0.20 mmol) of the compound from Example 7 were introduced into 11 ml of dichloromethane at 0° C., 49.2 mg (0.20 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. 2 ml of methanol were added, the residue after concentration was taken up in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases were separated, the organic phase was washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 50 mg (63% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].Cl.[NH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].C(N(CC)CC)C.[CH3:24][C:25]([C:28]1[CH:33]=[C:32]([SH:34])[CH:31]=[C:30]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:29]=1[OH:39])([CH3:27])[CH3:26]>ClCCl>[CH3:27][C:25]([C:28]1[CH:33]=[C:32]([S:34][CH2:3][CH2:2][C:1]([NH:7][CH2:8][C:9](=[O:10])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:4])[CH:31]=[C:30]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:29]=1[OH:39])([CH3:24])[CH3:26]
Reactant: NCC(=O)c1ccccc1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1cc(SCCC(=O)NCC(=O)c2ccccc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acryloyl chloride (2 ml) was added to a cold (5°) solution of 2-aminoacetophenone hydrochloride (4.6 g, 27 mmole) and triethylamine (7 ml) in dichloromethane (25 ml) and the mixture was stirred at room temperature. An additional 7 ml of triethylamine was added. After one hour, 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (11 g, 46 mmole) was added and the mixture heated to reflux. The mixture was allowed to cool to room temperature and the reaction mixture was washed sequentially with 10% hydrochloric acid and water, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel and recrystallization from ethyl acetate gave the title compound, m.p. 146°-148°. Analysis. Calcd. for C25H33NO3S: C, 70.22; H, 7.78; N, 3.28; S, 7.22. Found: C, 69.95; H, 7.93; N, 3.20; S, 7.62.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([CH3:22])[CH3:21].[I-].[K+]>C(OCC)(=O)C.[I-].[K+].CN(C)C=O>[CH:20]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6])([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc(C)c(O)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(OC(C)C)c1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
To a mixture of methyl 3-hydroxy-4-methylbenzoate (5.28 g, 31.8 mmol), potassium carbonate (6.59 g, 47.7 mmol) and N,N-dimethylformamide (50 mL) were added 2-bromopropane (3.58 mL, 38.2 mmol) and potassium iodide (0.53 g, 3.18 mmol) under stirring at room temperature, and the mixture was stirred at 80° C. for 7 hr. To the reaction mixture were added 2-bromopropane (1.79 mL, 19.1 mmol) and potassium iodide (0.27 g, 1.59 mmol), and the mixture was further stirred at 80° C. for 15 hr. The reaction mixture was allowed to cool, diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=19/1-hexane/ethyl acetate=4/1) to give the title compound (6.3 g, yield 96%) as a colorless oil.
Reaction SMILES: N1C=CN=N1.[N-]=[N+]=[N-].ClC1N=[C:17]2[C:13](NC=N2)=[C:12](Cl)N=1.C(N)C1C=CC=CC=1.[Cl:28][C:29]1[N:37]=[C:36]2[C:32]([NH:33][CH:34]=[N:35]2)=[C:31]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:30]=1.C(Br)C#C>CS(C)=O>[Cl:28][C:29]1[N:37]=[C:36]2[C:32]([N:33]=[CH:34][N:35]2[CH2:17][C:13]#[CH:12])=[C:31]([NH:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:30]=1
Reactant: Clc1nc(NCc2ccccc2)c2[nH]cnc2n1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C#CCBr
Agent: [N-]=[N+]=[N-]
Agent: c1c[nH]nn1
Solvent: CS(C)=O
Solvent: NCc1ccccc1
Product: C#CCn1cnc2c(NCc3ccccc3)nc(Cl)nc21
Reaction time: 0.25 h

Procedure:
In one example of the application, a triazole and its fluorinated derivatives can be prepared by a Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction of the corresponding alkyne and azide substrates. As shown below in Scheme 1, synthesis can begin with the reaction of 2,6-dichloropurine (Compound 3) with benzylamine (a) as described, for example, by Oumata, N. et al., Org. Process Res. Dev. 13:641-644 (2009). Using the conditions set forth in the Example below, the reaction can be completed in about 15 minutes at about 60° C. 2-chloro-6-benzylaminopurine (Compound 4) can be propargylated using propargyl bromide in DMSO under mild conditions to yield 2-chloro-6-benzylamino-9-(2-propynyl) purine (Compound 5). The Cu(I)-catalyzed azide-alyne click reaction (as described, for example, by Amblard, F. et al., Chem. Rev. 109:4207-4220, 2009) of 2-chloro-6-benzylamino-9-(2-propynyl) purine (Compound 5) with fluorinated benzyl azides (which can be prepared in situ from their corresponding benzyl bromides) can then yield 1,4-disubstituted triazoles or, more specifically, 2-chloro-6-benzylamino-9-[1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl-methyl]purine (Compound 7), 2-chloro-6-benzylamino-9-[1-(2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl-methyl]purine (Compound 8), and 2-chloro-6-benzylamino-9-[1-(pentafluorobenzyl)-1H-1,2,3-triazol-4-yl-methyl]purine (Compound 9).
Reaction SMILES: [C:1]([C:4](=[CH:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][CH3:8])=[O:6])(=O)[CH3:2].[NH2:15][C:16]1[N:20]=[CH:19][NH:18][N:17]=1>C(O)C>[CH3:8][O:7][C:5]([C:4]1[CH:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[N:17]2[N:18]=[CH:19][N:20]=[C:16]2[NH:15][C:1]=1[CH3:2])=[O:6]
Reactant: Nc1nc[nH]n1
Reactant: COC(=O)C(=Cc1cccs1)C(C)=O
Solvent: CCO
Product: COC(=O)C1=C(C)Nc2ncnn2C1c1cccs1
Yield: 44.9 %

Procedure:
A mixture of 50 g of methyl 2-acetyl-3-(2-thienyl)acrylate, 20 g of 3-amino-1,2,4-triazole and 300 ml of ethanol is heated under reflux for 4 hours. The precipitated white crystals are collected by filtration to give 29.5 g of 6-methoxycarbonyl-5-methyl-7-(2-thienyl)-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine, melting at 239°-240° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[C:16]([C:17]([C:19]4[C:20]([C:25]5[CH:26]=[C:27]6[C:31](=[CH:32][CH:33]=5)[CH2:30][CH:29]([NH2:34])[CH2:28]6)=[N:21][CH:22]=[CH:23][CH:24]=4)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:8]=2)[CH2:3]1.[C:35]1([CH3:45])[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1.C(N([CH2:51][CH3:52])CC)C>C(Cl)Cl>[C:35]1([CH3:45])[CH:40]=[CH:39][C:38]([S:41]([NH:34][CH:29]2[CH2:28][C:27]3[C:31](=[CH:32][CH:33]=[C:25]([C:20]4[C:19]([C:17]([C:16]5[C:11]([C:7]6[CH:8]=[C:9]7[C:4](=[CH:5][CH:6]=6)[CH2:3][CH:2]([NH:1][S:41]([C:38]6[CH:39]=[CH:40][C:51]([CH3:52])=[CH:36][CH:37]=6)(=[O:43])=[O:42])[CH2:10]7)=[N:12][CH:13]=[CH:14][CH:15]=5)=[O:18])=[CH:24][CH:23]=[CH:22][N:21]=4)[CH:26]=3)[CH2:30]2)(=[O:43])=[O:42])=[CH:37][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Reactant: NC1Cc2ccc(-c3ncccc3C(=O)c3cccnc3-c3ccc4c(c3)CC(N)C4)cc2C1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC2Cc3ccc(-c4ncccc4C(=O)c4cccnc4-c4ccc5c(c4)CC(NS(=O)(=O)c4ccc(C)cc4)C5)cc3C2)cc1

Procedure:
21 g of 2-aminoindan-5-yl-3-pyridyl ketone are dissolved together with 18.9 g of p-toluenesulphonic acid chloride in 250 ml of methylene chloride. Then 9.2 g of triethylamine are added dropwise. After 4 hours the suspension is rotary-evaporated to dryness. The residue is suspended in water, made alkaline with sodium hydroxide solution and then suction filtered.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][CH:20]=[C:19]3[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:34]C(OC(Cl)=O)C.Cl.C(OCC)C>ClCCCl>[ClH:34].[C:28]1([S:25]([C:19]2[C:18]3[C:22](=[CH:23][CH:24]=[C:16]([CH2:15][CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:17]=3)[NH:21][CH:20]=2)(=[O:26])=[O:27])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: O=S(=O)(c1ccccc1)c1c[nH]c2ccc(CCN3CCN(Cc4ccccc4)CC3)cc12
Agent: Cl
Solvent: CCOCC
Solvent: ClCCCl
Product: O=S(=O)(c1ccccc1)c1c[nH]c2ccc(CCN3CCNCC3)cc12

Procedure:
A stirred mixture of 5-[2-(4-benzylpiperazin-1-yl)ethyl]-3-(phenylsulfonyl)-1H-indole (0.110 g, 0.24 mmol) and 1-chloroethylchloroformate (0.05 mL, 0.36 mmlole) in 1,2-dichloroethane (2 mL) was heated to reflux for 12 hours. The reaction mixture was cooled and concentrated in vacuo to a brown glass. The glass was taken up in methanol (4 mL) and heated to reflux for 6 h, then cooled and concentrated in vacuo to a semi solid. This solid was dissolved in diethyl ether and treated with 1 N HCl in diethyl ether (0.22 mL, 0.22 mmol) to afford a white precipitate isolated by vacuum filtration. Mp: 220° C. MS (ES+): 370 (M+H).
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]1[CH:9]=[C:8]([C:10](=[O:13])[NH:11][CH3:12])[CH:7]=[C:6]([CH3:14])[C:5]=1[C:15]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]2[C:16]=1[CH2:17][CH2:18][C@H:19]2[O:25][C:26]1[CH:39]=[CH:38][C:29]2[C@H:30]([CH2:33][C:34]([O:36]C)=[O:35])[CH2:31][O:32][C:28]=2[CH:27]=1>C(O)C.O>[CH3:3][C:4]1[CH:9]=[C:8]([C:10](=[O:13])[NH:11][CH3:12])[CH:7]=[C:6]([CH3:14])[C:5]=1[C:15]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]2[C:16]=1[CH2:17][CH2:18][C@H:19]2[O:25][C:26]1[CH:39]=[CH:38][C:29]2[C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][O:32][C:28]=2[CH:27]=1
Reactant: CNC(=O)c1cc(C)c(-c2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)OC)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNC(=O)c1cc(C)c(-c2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
LiOH×H2O (3 mg) is added to a solution of methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-(methylcarbamoyl)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (20 mg) in ethanol (0.77 mL) and water (0.5 mL) and the mixture is stirred for 24 hours at room temperature. After concentration the mixture is diluted with water, acidified with aqueous citric acid solution and extracted with dichloromethane. The organic phase is dried (MgSO4) and the residue chromatographed on silica gel (cyclohexane/ethyl acetate 100:0→60:40) to give the title compound. Yield 11 mg, LC (method 20): tR=5.54 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:30])=[CH:6][C:7]2[N:11]=[C:10]([C:12]3[C:16]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])=[CH:15][N:14](C4CCCCO4)[N:13]=3)[NH:9][C:8]=2[CH:29]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]1[C:5]([F:30])=[CH:6][C:7]2[N:11]=[C:10]([C:12]3[C:16]([NH:17][C:18]([CH:20]4[CH2:21][CH2:22]4)=[O:19])=[CH:15][NH:14][N:13]=3)[NH:9][C:8]=2[CH:29]=1)[CH3:2]
Reactant: CCOc1cc2[nH]c(-c3nn(C4CCCCO4)cc3NC(=O)C3CC3)nc2cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2[nH]c(-c3n[nH]cc3NC(=O)C3CC3)nc2cc1F
Reaction time: 5 h
Yield: 61.4 %

Procedure:
A solution of cyclopropanecarboxylic acid [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide [90 mg, Reference Example 48(d)] in a 1/1 mixture of trifluoroacetic acid and dichloromethane (30 mL) was stirred for 5 hours and then evaporated. The residue was mixed with ethyl acetate (30 mL) and aqueous sodium bicarbonate (30 mL). The organic layer was evaporated to give cyclopropanecarboxylic acid [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide (44 mg). LC-MS (Method E): RT=2.34 minutes, 330 (M+H)+. (b) Tetrahydropyran-4-carboxylic acid [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazole-4-yl]amide
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH:7]([CH2:15]/[CH:16]=[CH:17]/[CH:18]=O)[CH2:6]2.[CH3:20][NH:21][S:22]([CH2:25][C:26](=O)[CH3:27])(=[O:24])=[O:23].[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:36]1[CH:18]=[CH:17][CH:16]([CH2:15][CH:7]2[CH2:6][C:5]3[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:8]2=[O:14])[C:25]([S:22]([NH:21][CH3:20])(=[O:24])=[O:23])=[C:26]1[CH3:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1cc2c(cc1OC)C(=O)C(C/C=C/C=O)C2
Reactant: NCc1ccccc1
Reactant: CNS(=O)(=O)CC(C)=O
Product: CNS(=O)(=O)C1=C(C)N(Cc2ccccc2)C=CC1CC1Cc2cc(OC)c(OC)cc2C1=O

Procedure:
The title compound 80 is prepared according to the procedure reported in Example 27 with aldehyde 79 (104.4 mg, 0.40 mmol), N-methyl-2-oxo-propane-1-sulfonamide [prepared as described by Builla et al in Tetrahedron 1998, 3589](60.4 mg, 0.40 mmol) and benzylamine (42.8 mg, 0.40 mmol) as reactants. Purification by column chromatography on SiO2 (gradient of EtOAc in Petroleum Ether) afford the title compound 80 as a yellow solid. (Yield 77.1 mg, 40%).
Reaction SMILES: [OH:1][C:2]1([CH3:17])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9]C(=O)OC(C)(C)C)[CH2:4][CH2:3]1.[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>ClCCl.O>[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[NH2:9][CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([CH3:17])([OH:1])[CH2:3][CH2:4]1
Reactant: CC1(O)CCC(CNC(=O)OC(C)(C)C)CC1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(O)CCC(CN)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of EXAMPLE 555A (0.75 g) in dichloromethane (3 mL) was added a few drops of water followed by trifluoroacetic acid (1.19 mL) and the reaction stirred at room temperature. After stirring for 2 hours, additional trifluoroacetic acid (0.5 mL) was added. After an additional 4 hours, the reaction mixture was concentrated and dried under high vacuum. The resulting oily solid was triturated with diethyl ether with sonication. Filtration and washing with diethyl ether gave the title compound as a mixture of cis and trans isomers.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[S:10]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11]1.O>C(Cl)Cl>[Br:1][CH2:2][C:3]([C:14]1[S:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=1)=[O:4]
Reactant: COC(=O)c1ccsc1
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1csc(C(=O)CBr)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of bromoacetyl bromide (13.52 g, 0.067 mol) in 20 ml of CH2Cl2 was added dropwise to a solution of aluminum chloride (13.4 g, 0.105 mol) in 50 ml of CH2Cl2 at 0° C. The mixture was stirred for 1 h at 0° C., and then a solution of methyl 3-thiophenecarboxylate (9.49 g, 0.067 mol) in CH2Cl2 (50 ml) was added dropwise. The stirring was continued for 12 h and then the mixture was poured over water and ice and extracted with CH2Cl2. The organic phase was washed twice with water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]4[CH:25]=[CH:24]C(C)=[CH:22][CH:21]=4)[N:14]=3)[O:11][CH:12]=2)=[CH:4][CH:3]=1.[C:27]1(B2OC(C)(C)C(C)(C)O2)[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].CO[CH2:50][CH2:51]OC>C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:27]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]=[C:10]([C:13]4[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]5[CH:21]=[CH:22][C:50]([CH3:51])=[CH:24][CH:25]=5)[N:14]=4)[O:11][CH:12]=3)=[CH:6][CH:7]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(Br)cc4)co3)cc2C)cc1
Reactant: COCCOC
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(C5=CCCCC5)cc4)co3)cc2C)cc1
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of 4-(4-bromophenyl)-2-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,3-oxazole (Example 75, 200 mg, 0.49 mmol), 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (158 μl, 0.74 mmol), sodium carbonate (0.49 ml, 2M aqueous solution, 0.98 mmol) and tetrakis(triphenylphosphino)palladium(0) (57 mg, 0.05 mmol) in 1,2-dimethoxyethane (3 ml) was heated to reflux for 18 h. After cooling to rt, the mixture was filtered over a pad of celite. The filtrate was diluted with ethyl acetate and successively washed with 0.1 N aqueous HCl and water. The organic layer was dried (MgSO4), filtered and concentrated to dryness. The crude material was purified by preparative HPLC to afford the title compound as a white solid (115 mg, 57%): 1H NMR (400 MHz, DMSO-d6) 8.60 (s, 1H), 7.78 (d, 2H), 7.49 (d, 2H), 7.17 (d, 2H), 7.08 (d, 2H), 6.67 (s, 1H), 6.23 (m, 1H), 5.37 (s, 2H), 2.41-2.37 (m, 2H), 2.28 (s, 3H), 2.27 (s, 3H), 2.22-2.17 (m, 2H), 1.77-1.70 (m, 2H), 1.64-1.59 (m, 2H); ES-MS m/z 410, HPLC RT (Method D) 3.48 min.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([CH2:11]C(=O)C)(=[O:10])[CH3:9].[CH3:15][C:16]([CH3:18])=[O:17].C(OO)(=O)C>>[C:1]1([C:6](=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:10])[OH:7].[C:16]1([CH:18]=[CH:11][C:8]([OH:10])=[CH:9][CH:15]=1)[OH:17]
Reactant: CC(=O)CC(C)=O
Reactant: Oc1ccccc1
Reactant: CC(C)=O
Agent: CC(=O)OO
Product: Oc1ccc(O)cc1
Product: Oc1ccccc1O
Reaction time: 0.7 h

Procedure:
A reaction flask having an inner volume of 100 ml and provided with a thermometer, a stirrer, a reflux condenser and a dropping funnel was charged with 32.0 g (0.34 mol) of phenol and 0.0642 g (0.2 percent by weight based on said phenol) of acetyl acetone. To the contents of the flask, 7.6 g (0.034 mol) of an acetone solution of 34.0 percent by weight of peracetic acid was introduced introudced dropwise while under agitation at a temperature of 80° C over a period of 20 minutes. After the termination of said dropwise introduction of peracetic acid, the reaction system was agitated at the same temperature for an additional period of 42 minutes to bring the reaction to completion. Thereafter, the reaction mixture was analyzed for unaltered phenol and formed pyrocatechol and hydroquinone by gas chromatography. The results were 29.10 g, 1.66 g, and 1.09 g respectively. These values indicate the conversion of phenol to be 9.06 percent and the selectivity for dioxy-benzene to be 73.5 percent relative to peracetic acid and 81.2 percent relative to phenol. From the reaction mixture, acetone, formed acetic acid and acetyl acetone were simultaneously recovered by distillation. When the recovered mixture was analyzed for acetyl acetone by means of gas chromatography, the acetyl acetone content was found be 0.0591 g. This value indicates the recovery ratio to be 92 percent.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH:8]([O:21][CH3:22])[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH:28]=[O:29].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCCCCC.C1C=CC=CC=1.O>[CH3:22][O:21][CH:8]([O:7][CH3:6])[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[C:10]=1[CH:28]([OH:29])[C:27]1[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:25]([O:24][CH3:23])[CH:26]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: COc1cc(C(OC)OC)cc(OC)c1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COc1ccc(C(O)c2c(C(OC)OC)cc(OC)c(OC)c2OC)cc1OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.2 %

Procedure:
136 ml of a 1.6M n-butyl lithium solution in hexane are added to a solution of 48.5 g of 3,4,5-trimethoxybenzaldehyde dimethyl acetal in 485 ml of benzene under stirring at 0° C. for about 20 minutes. The mixture is further stirred at 0° C. for 30 minutes, and 33.2 g of 3,4-dimethoxybenzaldehyde are added thereto. After stirring the mixture at 0° to 10° C. for 2 hours, 485 ml of water and 16 g of citric acid are added thereto. After shaking the mixture, the organic layer is separated therefrom, washed with water and evaporated under reduced pressure to remove solvent. 78.5 g of 2-(3,4-dimethoxy-α-hydroxybenzyl)-3,4,5-trimethoxybenzaldehyde dimethyl acetal are thereby obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1([F:54])[CH2:7][O:6][C:5]([NH:8]C(C2C=CC(OC)=CC=2)(C2C=CC=C(OC)C=2)C2C=CC=CC=2)=[N:4][C@@:3]1([C:33]1[N:38]=[C:37]([NH:39][C:40]([C:42]2[C:47]([Cl:48])=[CH:46][C:45]([C:49]([F:52])([F:51])[F:50])=[CH:44][N:43]=2)=[O:41])[CH:36]=[CH:35][C:34]=1[F:53])[CH3:32].C(O)(C(F)(F)F)=O.[NH4+].[OH-]>ClCCl>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:54])([F:1])[C@:3]([C:33]2[N:38]=[C:37]([NH:39][C:40]([C:42]3[C:47]([Cl:48])=[CH:46][C:45]([C:49]([F:52])([F:50])[F:51])=[CH:44][N:43]=3)=[O:41])[CH:36]=[CH:35][C:34]=2[F:53])([CH3:32])[N:4]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3nc(NC(=O)c4ncc(C(F)(F)F)cc4Cl)ccc3F)C(F)(F)CO2)(c2ccccc2)c2cccc(OC)c2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(c2nc(NC(=O)c3ncc(C(F)(F)F)cc3Cl)ccc2F)N=C(N)OCC1(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.9 %

Procedure:
3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [6-((R)-5,5-difluoro-2-{[(4-methoxy-phenyl)-(3-methoxy-phenyl)-phenyl-methyl]-amino}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide (80 mg, 0.104 mmol) was dissolved in dichloromethane (0.1039 ml), TFA (80.0 μl, 1.04 mmol) was added and the reaction mixture was stirred at rt for 18 hours. The reaction mixture was poured onto a mixture of ice ethyl acetate and NH4OH (w=25%). The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was chromatographed over silica gel (column 4 g, dichloromethane/methanol 95:5+0.5% ammonia) to give the title compound: 32 mg (65.9% yield).