Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[OH:16])[C:10]([OH:12])=[O:11]>>[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[C:15]=1[OH:16])[C:10]([OH:12])=[O:11]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Product: O=C(O)c1cc(Cl)c(O)c(S(=O)(=O)Cl)c1
Temperature: 65 °C
Yield: 74.2 %

Procedure:
To a flask charged with chlorosulfonic acid (13.9 mL, 209.0 mmol) was added 3-chloro-4-hydroxybenzoic acid (6.0 g, 34.8 mmol) portionwise over ten minutes. The mixture was then heated for 2 h at 65° C. under a nitrogen atmosphere. After cooling the mixture to room temperature, the reaction mixture was carefully poured over crushed ice with vigorous stirring, and extracted with Et2O until no further product remained in the aqueous layer. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 3-chloro-5-(chlorosulfonyl)-4-hydroxy-benzoic acid as a white solid (7.0 g, 74%) which was used without further purification.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[S:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.[Na].Br[CH2:21][C:22]([O:24]CC)=[O:23].Cl>O1CCCC1.O>[C:22]([CH2:21][O:3][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[S:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:24])=[O:23]
Reactant: CCOC(=O)CBr
Reactant: O=c1c2ccccc2sc2cccc(O)c12
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1cccc2sc3ccccc3c(=O)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
24 g sodium hydroxide was refluxed in 400 ml tetrahydrofuran for five minutes. 22.8 g (0.1 mols) hydroxythioxanthone was added and reflux continued for 1 hour, during which time the colour changed to bright red, indicating the formation of the sodium salt of hydroxythioxanthone. 35.1 g (0.21 mols) of ethyl bromoacetate was added and reflux was continued for three hours. After cooling to room temperature, 400 ml of deionised water were added with stirring, and the tetrahydrofuran was distilled out to yield a clear red solution. Reflux was continued for a further 2 hours in order to hydrolyse all the ester intermediate. The solution was then cooled to 50 C and 400 ml 1.0 M aqueous hydrochloric acid was added with stirring, causing the solid product to precipitate out. After refluxing for five minutes to be sure that all the sodium salt was converted to free acid, the solution was cooled to room temperature and stirred for two hours before filtering off the solid, washing with 400 ml deionised water and drying in a vacuum oven at 80 C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29](F)(F)F)[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC([C:49]3N(CCNC(C)C)[CH:51]=[C:52]([C:54]4C=CC(F)=C(C)C=4)[N:53]=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:49][NH:53][CH:52]([CH3:54])[CH3:51])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH3:29])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: Cc1cc(-c2cn(CCNC(C)C)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Product: Cc1cc(-c2cn(CCNC(C)C)c(C3CCN(c4ncnc(N)c4C(N)=O)CC3)n2)ccc1F

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-isopropylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=481, obsd.=481).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][C:15]#[CH:16])=[O:12])=[CH:4][CH:3]=1.[N:21]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=1)=[N+:22]=[N-:23].O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].C(O)(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][C:15]2[N:23]=[N:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:26]=3)[CH:16]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: C#CCNC(=O)c1cccnc1Nc1ccc(Br)cc1
Reactant: [N-]=[N+]=NCc1cccc(Oc2ccccc2)c1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(NCc1cn(Cc2cccc(Oc3ccccc3)c2)nn1)c1cccnc1Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 88 %

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-bromoaniline (9d, 172 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-bromophenylamino)-N-(prop-2-ynyl)nicotinamide 10d as pure product. To a solution of 2-(4-bromophenylamino)-N-(prop-2-ynyl)nicotinamide (10d, 150 mg, 0.45 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 112 mg, 0.5 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1d (220 mg 80%); mp: 160-162° C.; 1H NMR (300 MHz, CDCl3) δ 10.36 (s, 1H), 8.25 (dd, J=3.0, 1.5 Hz, 1H), 7.59 (m, 2H), 7.54 (s, 1H), 7.35-7.28 (m, 3H), 7.22 (brs, 1H), 7.11 (t, J=7.5 Hz, 1H), 7.03-6.94 (m, 7H), 6.67-6.63 (m, 1H), 5.45 (s, 2H), 4.64 ppm (d, J=6.0 Hz, 1H); MS (ESI m/z): 555 [M+H]+. Yield: 80%
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:12]3=[N:13][C:14]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[N:15][C:16](=[O:17])[C:11]3=[C:10]([CH3:24])[NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+].[N+:27]([O-])([OH:29])=[O:28]>>[N+:27]([C:4]1[CH:3]=[CH:2][C:1]([CH2:7][N:8]2[C:12]3=[N:13][C:14]([C:18]4[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=4)=[N:15][C:16](=[O:17])[C:11]3=[C:10]([CH3:24])[NH:9]2)=[CH:6][CH:5]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])O
Reactant: Cc1[nH]n(Cc2ccccc2)c2nc(-c3ccncc3)nc(=O)c1-2
Agent: [NH4+]
Agent: [OH-]
Product: Cc1[nH]n(Cc2ccc([N+](=O)[O-])cc2)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 91 %

Procedure:
To a solution of 90% nitric acid (30 ml) at -12°-0° C. was added in small portions 1-phenylmethyl-3-methyl-6-(4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-one (2.99 g, 9.4 mmol). The reaction mixture was stirred at 0° C. for 2.5 hours and then poured slowly into ice-water. The solution was neutralized with concentrated ammonium hydroxide to afford a yellow solid which was collected by filtration and washed with water, ethanol and finally ether. The product was recrystallized from ethyl acetate/ethanol (3×) to afford 3.2 g (91%) of 1-(4-nitrophenylmethyl)-3-methyl-6-(4-pyridyl)pyrazolo(3,4-d)pyrimidin-4-one as a white powder which is contaminated with a small amount of the meta isomer (ratio para/meta is 93/7). The mixture had a melting point of 275°-281° C. when dried at 125° C. for 24 hours in high vacuum.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[N+:13]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[C:3]2[C:10]([OH:12])=[O:11])([O-:15])=[O:14]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of indazole-3-carboxylic acid 16AP (10.5 g, 64.8 mmol) in concentrated sulfuric acid (125 ml) at 0° C. was added KNO3 (64.8 mmol, 6.55 g). The reaction mixture was warmed up to r.t. After stirring for 4 hr at r.t, it was poured into a 525 ml of ice/water. Solid was collected by filtration and washed with water to give desired 5-nitro-1H-indazole-3-carboxylic acid 17AP (10.74 g, 80%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([OH:25])=[C:7]([C:9]2[N:13]([CH:14]3[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]3)[N:12]=[CH:11][CH:10]=2)[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:34][C:35]1[C:36](F)=[CH:37][C:38]([F:61])=[C:39]([S:41]([N:44]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=2[O:59][CH3:60])[C:45]2[S:46][CH:47]=[N:48][N:49]=2)(=[O:43])=[O:42])[CH:40]=1.C(OC)(C)(C)C>CS(C)=O.O>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([O:25][C:36]2[CH:37]=[C:38]([F:61])[C:39]([S:41]([N:44]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=3[O:59][CH3:60])[C:45]3[S:46][CH:47]=[N:48][N:49]=3)(=[O:42])=[O:43])=[CH:40][C:35]=2[Cl:34])=[C:7]([C:9]2[N:13]([CH:14]3[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:17]3)[N:12]=[CH:11][CH:10]=2)[CH:8]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CC(n2nccc2-c2cc(C(F)(F)F)ccc2O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(C(F)(F)F)cc3-c3ccnn3C3CN(C(=O)OC(C)(C)C)C3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
tert-Butyl 3-[5-(5-trifluoromethyl-2-hydroxyphenyl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (Preparation 34, 400 mg, 1.04 mmol) and potassium carbonate (450 mg, 3.26 mmol) were combined in dimethylsulfoxide (5 mL). To this slurry was added 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 6, 482 mg, 1.04 mmol) and stirred at ambient temperature for 3 hours. tert-Butylmethyl ether (30 mL) and water (30 mL) were added and the layers separated. The organic layer was washed with water (2×30 mL), then dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give a foam. The foam was purified by silica gel flash column chromatography (20% to 40% ethyl acetate in heptane gradient elution) to afford the title compound as a colourless foam (600 mg, 70%).
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.Br[C:32]1[N:33]=[C:34]2[CH:40]=[C:39]([C:41]3[C:49]4[C:44](=[CH:45][CH:46]=[C:47]([O:50][CH3:51])[CH:48]=4)[N:43]([CH3:52])[CH:42]=3)[N:38]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[C:35]2=[N:36][CH:37]=1.[C:61](=[O:68])([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])[NH2:62].CC([O-])(C)C.[Na+]>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:51][O:50][C:47]1[CH:48]=[C:49]2[C:44](=[CH:45][CH:46]=1)[N:43]([CH3:52])[CH:42]=[C:41]2[C:39]1[N:38]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[C:35]2=[N:36][CH:37]=[C:32]([NH:62][C:61](=[O:68])[O:63][C:64]([CH3:67])([CH3:66])[CH3:65])[N:33]=[C:34]2[CH:40]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(Br)cnc3n1COCC[Si](C)(C)C)cn2C
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c(-c1cc3nc(NC(=O)OC(C)(C)C)cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 41.5 %

Procedure:
In a flask was added Pd2(dba)3 (0.094 g, 0.10 mmol) and di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.087 g, 0.21 mmol) in 1,4-dioxane (10 mL). The mixture was heated to about 80° C. for about 10 min. 2-Bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.500 g, 1.03 mmol, Preparation #C.1), tert-butyl carbamate (0.180 g, 1.54 mmol) and NaOt-Bu (0.148 g, 1.54 mmol) were then added and heating was continued for about 45 min. The mixture was cooled to rt and diluted with EtOAc (20 mL), washed with water (15 mL) and dried over MgSO4. The mixture was filtered and concentrated in vacuo and purified by a 12 g silica column eluting with 0 to 30% EtOAc/DCM to provide tert-butyl 6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.224 g, 42%): LC/MS (Table 2, Method g) Rt=1.99 min; MS m/z 524 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:9]2[C:5]([CH2:11][CH2:12][CH2:13][C:14]([O:16]CC3C=CC=CC=3)=[O:15])([CH2:6][CH2:7][C:8]2=[O:10])[CH2:4][CH2:3]1.[H][H]>O1CCCC1.[Pd]>[O:10]=[C:8]1[N:9]2[C:5]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])([CH2:4][CH2:3][C:2]2=[O:1])[CH2:6][CH2:7]1
Reactant: O=C(CCCC12CCC(=O)N1C(=O)CC2)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)CCCC12CCC(=O)N1C(=O)CC2

Procedure:
A solution of 1.0 g (0.0032 mole) tetrahydro-3,5-dioxo-1H-pyrrolizine-7a(5H)-butanoic acid, benzyl ester, prepared in Example I in tetrahydrofuran (30 ml) is treated with hydrogen in the presence of 0.1 g of a 20% Pd/C catalyst. The resulting solution is filtered to remove the catalyst and the product crystallizes upon concentration. Recrystallization from acetonitrile yields tetrahydro-3,5-dioxo-1H-pyrrolizine-7a(5H)-butanoic acid with a melting point of 178°-180° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O=[C:8]1[C:14]2=[N:15][CH:16]=[CH:17][N:13]2[CH2:12][C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=2[NH:9]1.O.[OH-].[Na+]>O1CCCC1>[N:15]1[CH:16]=[CH:17][N:13]2[CH2:12][C:11]3[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=3[NH:9][CH2:8][C:14]=12
Reactant: O=C1Nc2ccccc2Cn2ccnc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(c1)Cn1ccnc1CN2
Temperature: 0 °C

Procedure:
To a suspension of 4 mmol of lithium aluminum hydride in 20 ml of anhydrous tetrahydrofuran is added a 1 mmol solution of 10,11-dihydro-11-oxo-5H-imidazo[2,1-c][1,4]benzodiazepine and the mixture is refluxed for 24 hours and cooled at 0° C. To the mixture is added dropwise 0.12 ml of water and 6 ml of 1N sodium hydroxide. The mixture is extracted with ethyl acetate and the solvent removed to give the desired product as a solid. Recrystallization from methylene chloride-hexane gives crystals, m.p. 164°-170° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH2:7])[CH2:2]1.[Cl-].[Na+].[OH-].[Na+].[CH3:12][NH:13][C:14](=[N:17][N+:18]([O-:20])=[O:19])OC.Cl>O>[CH3:12][NH:13][C:14]([NH:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[N:17][N+:18]([O-:20])=[O:19]
Reactant: CNC(=N[N+](=O)[O-])OC
Reactant: NCC1CCOC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CNC(=N[N+](=O)[O-])NCC1CCOC1
Reaction time: 4 h
Yield: 81.5 %

Procedure:
[(3-tetrahydrofuryl)methyl]amine (43.3 g, 0.43 mole), 31.3 g of sodium chloride and 125 g of water were mixed, and the resulting mixture was cooled to −10 degree centigrade. Furthermore, 2.9 g (0.07 mole) of 96% NaOH was added to the solution and dissolved. Sodium chloride was dissolved in water with 76% of the saturated solubility at a water temperature of −10 degree centigrade. N,O-dimethyl-N′-nitroisourea (49.2 g, 0.37 mole) was introduced into the above solution, stirred at −10 degree centigrade for 4 hours, and then heated to 0 degree centigrade and further stirred for 18 hours. 35% hydrochloric acid (13.1 g, 0.13 mole) was added to the suspension so that the pH became not more than 4. The suspension was heated and dissolved for carrying out recrystallization. The precipitated crystal was filtered, and the filtered crystal was washed with cold water and then dried. 61 g of a 1-methyl-2-nitro-3-[(3-tetrahydrofuryl)methyl]guanidine with a purity of 99% was obtained. The isolated yield at this time was 81%.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[O:18][CH:19]2[OH:27])[C@H:14]2[O:29][C@@H:13]32)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].[ClH:30].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[O:18][CH:19]2[OH:27])[C@H:14]([Cl:30])[C@H:13]3[OH:29])[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@@H]4O[C@@H]4C4=CC(=O)OC(O)[C@]4(C)[C@H]3CC[C@@]21C
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@H](O)[C@@H](Cl)C4=CC(=O)OC(O)[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 20 mg of 17α-acetoxy-6α,7α-epoxy-1ξ-hydroxy-2-oxa-4-pregnene-3,20-dione and 3 ml of 16% hydrochloric acid/ethyl acetate solution was stirred at room temperature for 10 minutes. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated to give 21 mg of 17α-acetoxy-6β-chloro-1ξ,7α-dihydroxy-2-oxa-4-pregnene-3,20-dione.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]([CH2:21]Cl)[CH:18]=[CH:17][C:3]=1[O:4][CH2:5][C:6]1[N:7]=[C:8]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[O:9][C:10]=1[CH3:11].[CH2:23]([N:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:32]([OH:40])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([N:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:32]([O:40][CH2:21][C:19]2[CH:18]=[CH:17][C:3]([O:4][CH2:5][C:6]3[N:7]=[C:8]([C:12]4[O:13][CH:14]=[CH:15][CH:16]=4)[O:9][C:10]=3[CH3:11])=[C:2]([Br:1])[CH:20]=2)=[N:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cc1Br
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(Br)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
A mixture of 4-{[2-bromo-4-(chloromethyl)phenoxy]methyl}-2-(2-furyl)-5-methyl-1,3-oxazole (3.52 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (2.27 g), potassium carbonate (1.27 g) and N,N-dimethylformamide (100 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give ethyl 1-benzyl-3-[(3-bromo-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (5.17 g, yield 95%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 158-159° C.
Reaction SMILES: [H-].[Na+].CO[C:5](=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13].[C:15](#[N:17])[CH3:16]>C1(C)C=CC=CC=1>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]([CH2:16][C:15]#[N:17])=[O:14]
Reactant: COC(=O)c1ccccc1OC
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccccc1C(=O)CC#N
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Into an agitation apparatus with agitator, dropping funnel, gas inlet tube and reflux cooler, under agitation and introduction of nitrogen, 28.8 g (0.6 mol) sodium hydride (as a 50 wt-% suspension in white oil) suspended in 200 ml absolute toluene and 49.9 g (0.3 mol) 2-methoxybenzoic acid methyl ester were introduced. The mixture was heated to 85° C. Within 2 hr, 24.6 g (0.5 mol) absolute acetonitrile was dropped into the heated mixture. Then the reaction mixture was further agitated for 15 hr at 90° C. The mixture was then cooled to 0° C., 300 ml ice water were added carefully under vigorous agitation, and then agitation was continued for 1 hr at 0° C. Then the aqueous phase was removed and extracted with 100 ml toluene. After cooling to 0° C. the aqueous phase was acidified with dilute hydrochloric acid to pH 1. The precipitated product was washed with ice water and dried. The crude product (44 g) was recrystallized from isopropanol; 37.9 g (72% of the theoretical) 2-methoxybenzoylacetonitrile with m.p. 85°-88° were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([O:6][CH3:7])[C:4]=1[Cl:11].[CH3:12][O:13]C(Cl)Cl.O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Cl:11][C:4]1[C:3]([O:2][CH3:1])=[C:10]([CH:9]=[CH:8][C:5]=1[O:6][CH3:7])[CH:12]=[O:13]
Reactant: COC(Cl)Cl
Reactant: COc1cccc(OC)c1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C=O)c(OC)c1Cl

Procedure:
2-chlororesorcinol dimethyl ether (3.4 g) is dissolved in 20 ml of CH2Cl2 and TiCl4 (4.3 ml) is added. To this solution is added dichloromethyl methyl ether (2.3 g). After 30 minutes the reaction mixture is poured into H2O into H2O and extracted with ether. Drying and evaporation gives 3-chloro-2,4-dimethoxybenzaldehyde, mp 107°-108° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9](O)=[O:10])[CH:7]=1.[NH2:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([NH:26][C:27]2[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:29][CH:28]=2)=[O:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CC(C)CC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C)CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
87 mg (0.23 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methylpentanoic acid (racemate) and 49 mg (0.25 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 45 mg (35% of theory)
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[O:5]=[O+][O-]>>[CH3:4][C:2]1([O:5][CH2:3]1)[CH3:1].[CH3:3][C:2](=[CH2:1])[CH3:4]
Reactant: O=[O+][O-]
Agent: C=C(C)C
Product: CC1(C)CO1

Procedure:
A stream of renewable isobutylene (95% from a dehydration reactor fed renewable isobutanol), is heated to 350° C. at 0.25 atm in the presence of 0.4 equivalents of ozone to produce a stream of 1 part isobutylene oxide and 2 parts isobutylene. The stream is partially cooled and fed through a flow reactor charged with niobic acid catalyst at a rate of 40-60 g/hr at 225° C. Enough pressure (600 psi) is applied to keep the reactants in the liquid phase. The excess gas collected is primarily isobutylene and is recycled back to mix with an enriched isobutylene oxide stream to ensure the 1:2 stochiometry detailed above. The liquid effluent is sampled for conversion to 2,5-dimethyl-2,4-hexadiene, which is normally 65% with the remainder being unreacted starting material and a minor portion (5%) of higher isobutylene oligomers. At optimal conditions the reactor is continually run for periods longer than 10 days.