Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:45]=[CH:46][CH:47]=2)[CH2:33][CH2:34][C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([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)=CC=1>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:30]3[CH:31]=[C:32]([CH:45]=[CH:46][CH:47]=3)[CH2:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:43][CH:44]=3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COC(=O)c1ccc(CCc2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(CCc2cccc(-c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)c2)cc1
Yield: 56.3 %

Procedure:
To a stirred solution of 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (88 mg, 0.27 mmol) and methyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)benzoate (100 mg, 0.27 mmol) in 25 mL of 1,4-dioxane were added Na2CO3 (100 mg, 0.94 mmol) and 3 mL of water at room temperature. Then the mixture was degassed with nitrogen for 15 minutes. Pd(PPh3)4 (20 mg, 0.017 mmol) was added in one portion and the reaction mixture was stirred at reflux for 18 hours under nitrogen. The solvent was evaporated and the residue was purified by silica gel chromatography (200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate=1:1) to give methyl 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)phenethyl)benzoate (80 mg, 56%) as a yellow sold. LC-MS: 527 [M+H]+, tR=1.87 min.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/C3C=CC=C(Cl)C=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:20]([O:22][CH:23]=[CH:24][C:25](=[CH2:31])[O:26][Si](C)(C)C)[CH3:21]>C1(C)C=CC=CC=1>[CH2:20]([O:22][CH:23]1[C:6]2([C:5]3[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:12][CH2:26][C:25](=[O:31])[CH2:24]1)[CH3:21]
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1
Reactant: C=C(C=COCC)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC1CC(=O)CCC12C(=O)Nc1ccccc12
Temperature: 140 °C
Reaction time: 16 h
Yield: 23.7 %

Procedure:
To a suspension of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one (1.45 g, 15.0 mmol) in toluene (20 mL) in a sealed tube was added (3-ethoxy-1-methylene-allyloxy)-trimethyl-silane (1.24 g, 7.5 mmol). The reaction mixture was allowed to stir at 140° C. for 16 hrs. The solvent was removed by concentration. The residue was dissolved in MeOH (50 mL) and treated with 4 N NaOH (5 mL) at rt for 0.5 h. The reaction mixture was then diluted with AcOEt and washed with water and brine. After concentration the residue was purified by flash column (5%-30% AcOEt in Hex) to give a mixture (1.2 g) of rac-(1R,2R)-6′-chloro-2-(3-chlorophenyl)spiro[5-cyclohexene-1,3′-[3H]indole]-2′,4(1′H)-dione and rac-(1R,2S,6R)-6′-chloro-2-3-chlorophenyl)-6-ethoxy-spiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione (0.46 g, 18.6%) as white amorphous which was used for next steps without further purification. A small amount mixture was separated by normal phase HPLC gave rac-(1R,2S,6R)-6′-chloro-2-(3-chlorophenyl)-6-ethoxy-spiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione. MS+:358 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH2:9][C:10](N)=[O:11])=[C:6]([Cl:13])[N:5]=[C:4](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[CH3:22][CH2:23][OH:24]>>[NH2:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:24][CH2:23][CH3:22])=[O:11])=[C:6]([Cl:13])[N:5]=[C:4](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1
Reactant: CCO
Reactant: NC(=O)CCc1c(N)nc(/C=C/c2ccccc2)nc1Cl
Product: CCOC(=O)CCc1c(N)nc(/C=C/c2ccccc2)nc1Cl
Temperature: 25 °C

Procedure:
3-{4-Amino-6-chloro-2-[(E)-2-phenylethenyl]-5-pyrimidinyl}propanamide (0.175 g, 0.58 mmol) was dissolved in EtOH (15 mL) and HCl gas was bubbled through the solution until saturated. The solution was heated at reflux for 2 h, cooled to ambient temperature and concentrated under vacuum. The residue was dissolved in water and extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4, filtered and concentrated under vacuum to yield ethyl 3-{4-amino-6-chloro-2-[(E)-2-phenylethenyl]-5-pyrimidinyl}propanoate as a white solid. LCMS: m/z 332.2 (MH+). This product was then dissolved in DMF (5 mL), treated with K2CO3 (0.16 g, 1.16 mmol) and heated at 75° C. for 30 minutes. The solution was cooled, diluted with water and extracted with Et2O (3×). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was then purified by column chromatography (silica gel) to yield an additional 0.11 g of the desired compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5](I)=[CH:4][N:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1cccs1
Reactant: OCCNc1nc(Cl)ncc1I
Product: OCCNc1nc(Cl)ncc1-c1cccs1
Yield: 82 %

Procedure:
In the reaction of 2-(2-chloro-5-iodopyrimidine-4-ylamino)-ethanol (300 mg, 1.0 mmol) with thiophen-2-boronic acid (140 mg, 1.1 mmol) according to procedure 3, the desired product is obtained in 82% yield (210 mg) after chromatographic purification (silica gel, ethyl acetate/hexane (0%-100% ethyl acetate)).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].C([O-])([O-])=O.[Na+].[Na+].[C:20]1([CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH:7][C:27](=[O:28])[CH:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: Cc1cccc(C[C@H](N)C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C[C@H](NC(=O)C(c2ccccc2)c2ccccc2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-methyl-L-phenylalanine (1.8 g, 10.06 mmol) and Na2CO3 (3.2 g, 3.0.18 mmol) in water (150 mL) is added a solution of diphenylacetyl chloride (2.32 g, 10.06 mmol) in THF (150 mL), and the resulting solution is stirred vigorously at room temperature overnight. The THF is then evaporated and the aqueous layer is diluted with 6% aqueous Na2CO3 (100 mL), and washed with Et2O (3×150 mL). The aqueous layer is then acidified to pH 1 with conc. HCl, and the resulting slurry is extracted with EtOAc (3×100 mL). The organic phase is then washed with water (2×100 mL) and brine (1×100 mL), dried over MgSO4 and evaporated to yield 3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanine, as a white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22][CH2:23][OH:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.N1C=CC=CC=1.Cl[C:36]([O:38][CH3:39])=[O:37]>O>[C:36](=[O:37])([O:24][CH2:23][CH2:22][CH:21]([N:19]1[CH:20]=[C:16]([C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:27])([CH3:1])[CH3:28])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:17]=[N:18]1)[CH2:25][CH3:26])[O:38][CH3:39]
Reactant: CCC(CCO)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: COC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCC(CCOC(=O)OC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reaction time: 3 h

Procedure:
To a solution of [3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentan-1-01 (50 mg, 0.0001 mol) from Example 498 Step 2 in pyridine (1 mL, 0.01 mol), methyl chloroformate (30 μL, 0.0003 mol) was added. The reaction was stirred for 3 h, water was added and the product was extracted with ethyl acetate. The combined organic layers were washed 1N HCl, brine, dried over magnesium sulfate, filtered and concentrated to give methyl 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentyl carbonate as a semisolid residue (30 mg, 50%). LC/MS (M+H)+: m/z=460.
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[CH:3][C:2]=1[CH3:9].C1C(=O)N([Br:17])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:9][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[C:6]([CH3:7])[N:1]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)nc(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(C)nc(CBr)c1
Temperature: 0 °C

Procedure:
A solution of 2,4,6-collidine (1 mmole) in carbon tetrachloride was treated with NBS (5 mmole) and dibenzoyl peroxide (0.25 mmole) at 80° C. for 12 h. The reaction mixture was cooled to 0° C. and the precipitate was filtered. The filtrate was concentrated under vacuum. Chromatography gave 2-bromomethyl-4,6-dimethylpyridine.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[CH:20][C:21](=[O:25])[NH:22][C:23]=2[CH3:24])=[CH:14][CH:13]=1)=O)C1C=CC=CC=1.[BrH:26].C(O)C>C(O)(=O)C>[BrH:26].[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:19]=[CH:20][C:21](=[O:25])[NH:22][C:23]=2[CH3:24])=[CH:16][CH:17]=1
Reactant: Cc1[nH]c(=O)cnc1-c1ccc(NC(=O)OCc2ccccc2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1[nH]c(=O)cnc1-c1ccc(N)cc1

Procedure:
5-(4-Benzyloxycarbonylaminophenyl)-6-methyl-2(1H)-pyrazinone (0.5 g) was treated with hydrogen bromide in acetic acid in a manner similar to that described in Example 20 to give the title compound as its hydrobromide salt (340 mg) which after digestion with hot ethanol had m.p. >300° C.; δ(D2O) inter alia 2.39 (3H, d, CH3), 8.03 (1H, q, pyrazinone ring 3-H); ν(KBr) 1705, 1750 cm-1.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][CH:6]1[CH2:10][CH2:9][C:8]2([C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]2([CH3:19])[OH:18])[O:7]1.CN(C)C1C=CC=CC=1.OS(O)(=O)=O>CCOCC>[C:1]([O:18][C:11]1([CH3:19])[CH2:12][CH2:13][CH2:14][C:15]([CH3:17])([CH3:16])[C:8]21[O:7][CH:6]([CH3:5])[CH2:10][CH2:9]2)(=[O:3])[CH3:2]
Reactant: CC1CCC2(O1)C(C)(C)CCCC2(C)O
Reactant: CC(=O)Cl
Agent: O=S(=O)(O)O
Solvent: CN(C)c1ccccc1
Solvent: CCOCC
Product: CC(=O)OC1(C)CCCC(C)(C)C12CCC(C)O2
Reaction time: 48 h

Procedure:
5.9 g (0.079 M) of acetyl chloride were added over 30 minutes at 20° to a mixture of 2,6,10,10-tetramethyl-1-oxa-spiro[4.5]decan-6-ol -- isomer A; see Example 1 -- and 10.9 g of N,N-dimethylaniline. After having been kept for 2 days at room temperature the reaction mixture was heated to reflux during 3 hours, then cooled and treated with 50 ml of ether. The reaction mixture was then filtered and the clear filtrate thus obtained poured onto crushed ice and finally acidified with a 10 % aqueous solution of H2SO4. The organic layer was then washed with NaHCO3 in water, dried, evaporated and subjected to a fractional distillation to give 2.5 g of a product having b.p. 90° - 100°/0.1 Torr. After crystallisation in aqueous ethanol 1.9 g (75%) of the desired ester were isolated -- isomer A.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10])[N:3]=[N:2]1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=2)=[O:20])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][C:9]([NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[C:25]([CH3:30])[CH:26]=[C:27]([CH3:29])[CH:28]=3)=[O:20])[CH2:17][CH2:18]2)=[O:10])[N:3]=[N:2]1
Reactant: Cc1cc(C)cc(COC(=O)N2CCC(N)CC2)c1
Reactant: O=C(Cl)CCCc1c[nH]nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C)cc(COC(=O)N2CCC(NC(=O)CCCc3c[nH]nn3)CC2)c1
Reaction time: 3 h

Procedure:
To a stirred solution of 4-(1H-1,2,3-triazol-4-yl)butanoic acid chloride in DCM (5 ml) at RT (168 mg, 0.967 mmol) was added 3,5-dimethylbenzyl 4-aminopiperidine-1-carboxylate (318 mg, 1.064 mmol) and Huenig's Base (0.338 mL, 1.934 mmol) and the reaction mixture was allowed to stir for 3 hrs. The reaction mixture was diluted with DCM and washed with a saturated solution of brine. The layers were separated and the organic portion dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-10% MeOH in DCM as eluent to afford the title product;
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]([C:11]#[C:12][CH3:13])[C:7]([NH2:10])=[N:8][CH:9]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>CN1C(=O)CCC1>[Br:3][C:4]1[N:5]=[C:6]2[CH:11]=[C:12]([CH3:13])[N:10]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[C:7]2=[N:8][CH:9]=1
Reactant: CC#Cc1nc(Br)cnc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)n2c(C)cc3nc(Br)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
To a slurry of NaH (60% dispersion in mineral oil, 2.00 g, 49.9 mmol) in NMP (100 mL) was slowly added a solution of 5-bromo-3-(prop-1-ynyl)pyrazin-2-amine (7.05 g, 33.2 mmol) in NMP (20 mL). The reaction mixture was stirred at ambient temperature for about 20 min and then a solution of p-toluenesulfonyl chloride (6.97 g, 36.6 mmol) in NMP (20 mL) was added. The reaction mixture was stirred at ambient temperature for about 20 h and then aqueous HCl (1 N, 100 mL) was added to the reaction mixture. The resulting solids were collected by filtration. The brown solid was triturated with DCM/EtOAc (1:1, 30 mL) and collected by filtration to provide 2-bromo-6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (9.0 g, 74%) as a brown solid: LC/MS (Table 1, Method a) Rt=2.68 min; MS m/z: 366, 368 (1:1) (M+H)+.
Reaction SMILES: [OH:1][N:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]1=[S:8].C(=O)([O-])O.[Na+].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[C:14]([O:1][N:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]1=[S:8])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1csc(=S)n1O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1csc(=S)n1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.735 parts of 3-hydroxy-4-methylthiazol-2(3H)-thione were stirred in 50 parts of water and 0.84 parts of sodium hydrogen carbonate. The solution was screened and 0.9 parts of benzoyl chloride were added. The reaction mixture was stirred overnight at room temperature. A precipitate was formed which was separated by filtration, washed with cold water and recrystallised from ethanol to give 3-benzoyloxy-4-methylthiazol-2(3H)-thione, m.pt. 100°-102° C. By analysis the composition was found to be C, 52.4% wt; H, 3.6% wt; N, 5.6% wt and S, 25% wt. C11H9NO2S2 requires C, 52.6% wt; H, 3.6% wt; N, 5.6% wt and S, 25.5% wt.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH:11]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl>[CH:11]1([C:17]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([NH2:10])=[O:9])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NC(=O)c1ccccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1ccccc1NC(=O)C1CCCCC1

Procedure:
Anthranilamide was treated with cyclohexanecarbonyl chloride and triethylamine in dichloromethane, followed by washing (10% citric acid; water; sat. sodium bicarbonate; and sat. sodium chloride) and evaporated to give a nearly quantitative yield of 2-(cyclohexylcarbonylamino)benzamide as a white solid, which was used immediately in the next step.
Reaction SMILES: COCCOC.Br[CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([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)=CC=1.O>[F:19][C:20]1[CH:25]=[C:24]([CH:23]=[CH:22][CH:21]=1)[CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1
Reactant: CCOC(=O)c1cc(CBr)on1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cc(Cc2cccc(F)c2)on1
Yield: 60.9 %

Procedure:
1,2-Dimethoxyethane (8 mL) and water (2 mL) were added to the mixture of ethyl 5-(bromomethyl)isoxazole-3-carboxylate (0.710 g; 3.03 mmol), 3-fluorophenylboronic acid (0.481 g; 3.34 mmol), tetrakis(triphenylphosphine)palladium(0) (0.176 g; 0.151 mmol) and sodium carbonate (0.646 g, 6.07 mmol). The mixture was irradiated in a microwave oven at 130° C. for 15 min and was evaporated. The residue was partitioned between dichloromethane (30 mL) and brine (20 mL). The organic layer was separated and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 15 to 100% of dichloromethane in heptane) to afford 0.460 g (61%) of ethyl 5-(3-fluorobenzyl)isoxazole-3-carboxylate as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][N:5]([CH3:7])[CH:6]=1.O.[C:10]([OH:18])(=[O:17])[C:11]([CH2:13][C:14](O)=[O:15])=[CH2:12]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([N:8]2[C:14](=[O:15])[CH2:13][CH:11]([C:10]([OH:18])=[O:17])[CH2:12]2)=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)c(N)n1
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1cc(Br)c(N2CC(C(=O)O)CC2=O)n1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
To a solution of 4-bromo-1-methyl-1H-pyrazol-3-amine (312 mg) in a mixed solvent of water (2.0 mL) and toluene (2.0 mL) was added itaconic acid (245 mg). The reaction mixture was stirred at 120° C. for 5 hr, and the solvent was evaporated under reduced pressure. The residue was used for the next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[S:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[S:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1csc(-c2cccs2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1csc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)cs2)c1
Yield: 79 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(2-thienyl)thiazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienyl)thiazole. The yield was 79%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 76-77° C.
Reaction SMILES: C[Mg]Cl.[CH3:4][C:5](=[C:10]([CH3:12])[CH3:11])[C:6](=[CH2:9])[CH:7]=[O:8].[C:13](O)(=O)C>C1COCC1>[CH3:4][CH:5]([CH:10]([CH3:12])[CH3:11])[C:6](=[CH2:9])[CH:7]([OH:8])[CH3:13]
Reactant: CC(=O)O
Reactant: C=C(C=O)C(C)=C(C)C
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: C=C(C(C)O)C(C)C(C)C
Temperature: 17.5 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
Methylmagnesium chloride in THF (3 M, 2.65 L) was charged into a flame-dried 2-L reaction flask fitted with a mechanical stirrer, a thermocouple, a condenser, and a dropping funnel. The reaction flask was cooled with an external bath to about 15-20° C. 3,4-Dimethyl-2-methylene-pentenal (prepared as above) (834 g) was fed over about 2-3 hours to allow the exotherm temperature at about 30-35° C. After the feeding was completed, the reaction mass was aged for about 2 hours. GC analysis determined a conversion rate of about 95%. The reaction mixture was poured into a mixture of ice and acetic acid (500 g). The organic layer was separated and washed sequentially with brine (500 mL) and sodium carbonate (5%, 300 mL), and further fractional distilled to provide 4,5-dimethyl-3-methylene-hexan-2-ol (804 g) with a boiling point of 110° C. at 60 mmHg.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[C:21]1[N:22]=[N:23][C:24]([CH3:27])=[CH:25][N:26]=1.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=1>O1CCCC1>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]([OH:34])[CH2:27][C:24]2[N:23]=[N:22][C:21]([C:15]3[C:14]([F:13])=[CH:19][CH:18]=[CH:17][C:16]=3[F:20])=[N:26][CH:25]=2)=[CH:31][CH:30]=1
Reactant: Cc1cnc(-c2c(F)cccc2F)nn1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC(Cc1cnc(-c2c(F)cccc2F)nn1)c1ccc(Cl)cc1
Temperature: -50 °C
Reaction time: 2 h

Procedure:
At −20° C., 1.5 ml of n-butyllithium (1.6M in hexane) are added to 202 mg of diisopropylamine in 6 ml of tetrahydrofuran. After 15 min. the reaction mixture is cooled to −50° C. and 0.414 g of 3-(2,6-difluorophenyl)-6-methyl-[1,2,4]triazine in 2 ml of tetrahydrofuran is added dropwise. After 20 min. the mixture is cooled to −70° C., 0.281 g of 4-chlorobenzaldehyde in 3 ml of tetrahydrofuran is added dropwise and the mixture is then stirred at −70° C. for 2 h. The reaction mixture is then poured into ice-water and extracted with ethyl acetate; the organic phase is concentrated and the residue is purified by means of flash chromatography. In this way 1-(4-chlorophenyl)-2-[3-(2,6-difluorophenyl)-[1,2,4]triazin-6-yl]-ethanol is obtained in the form of a light-brown resin. After recrystallisation from diethyl ether/hexane, 1-(4-chlorophenyl)-2-[3-(2,6-difluorophenyl)-[1,2,4]triazin-6-yl]-ethanol is obtained in the form of beige crystals having a melting point of 98-102° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH2:6]O.[ClH:12].C(OC(C)C)(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH2:6][Cl:12]
Reactant: COc1cc(CO)ccc1C
Reactant: Cl
Solvent: Cc1ccccc1
Solvent: CC(C)OC(C)C
Product: COc1cc(CCl)ccc1C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 3-methoxy-4-methylbenzylalcohol (41.61 g), conc. hydrochloric acid (125 ml) and toluene (83 ml) was stirred at 90° C. for 1 hour. After cooling, ice-water (125 ml) and diisopropyl ether (80 ml) were added to the mixture, and the organic layer was separated, and the aqueous layer was extracted with diisopropyl ether (160 ml). The combined organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over sodium sulfate, and evaporated in vacuo to give 3-methoxy-4-methylbenzyl chloride (46.35 g) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14]O)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:16][NH:17][CH3:18]>C(O)C.ClCCl>[CH3:16][N:17]([CH3:18])[CH2:14][CH2:13][S:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:12])=[O:11]
Reactant: CNC
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Solvent: CCO
Solvent: ClCCl
Product: CN(C)CCS(=O)(=O)c1cccc([N+](=O)[O-])c1
Yield: 59.6 %

Procedure:
2-(3-Nitro-phenylsulfonyl)-ethanol (0.5 g; 2.6 mmol) was dissolved in 3 mL ethanol and 2 mL of dichloromethane. Then 1 mL of (7.8 mmol) dimethylamine (33% in ethanol) was added, the reaction mixture was subsequently concentrated in vacuo, dissolved in dichloromethane, and the product was precipitated by adding diethyl ether and petrol ether. 0.4 g (1.55 mmol; 59% yield) of dimethyl-[2-(3-nitro-benzenesulfonyl)-ethyl]-amine were obtained as a yellow solid.