Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:17])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[Br:16])[CH2:2][CH3:3].C(=O)(O)[O-].[Na+]>C(O)C.Cl.[Fe]>[CH2:1]([O:4][C:5](=[O:17])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[Br:16])[CH2:2][CH3:3]
Reactant: CCCOC(=O)Nc1ccc([N+](=O)[O-])cc1Br
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: CCCOC(=O)Nc1ccc(N)cc1Br
Yield: 84.9 %

Procedure:
A suspension of iron powder (20 g, excess) and (2-Bromo-4-nitrophenyl)-carbamic acid propyl ester (2.183 g, 7.20 mmol) in ethanol (80 mL) and 6 M aqueous hydrochloric acid (20 mL) was sonicated at room temperature for 10 minutes. The mixture was slowly poured into saturated aqueous sodium bicarbonate (NaHCO3) solution, filtered and extracted with ethyl acetate. The combined organic solution was washed 3 times with saturated aqueous NaHCO3, dried over sodium sulfate (Na2SO4) and evaporated in vacuo to give 1.67 g of the title compound as pale yellow oil which solidified. Yield 85%. LC/MS (m/z) 271.9, 273.8 (M+); RT=1.30, (UV, ELSD) 99%, 100%. 1H NMR (DMSO-d6): 0.90 (br. s (unresolved t), 3H), 1.59 (br. s (unresolved m), 2H), 3.94 (t, 2H), 5.31 (s, 2H, NH2), 6.50 (dd, 1H), 6.80 (unresolved d, 1H), 6.96 (br. d, 1H), 8.51 (br. s, NHCO).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:11][C:12]1[C:17](B(O)O)=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:11][C:12]1[C:17]([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: OB(O)c1cccnc1F
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: COCCOC
Product: Fc1ncccc1-c1ncnc2[nH]ccc12
Temperature: 25 °C
Yield: 17 %

Procedure:
A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (7.68 g, 50 mmol), 2-fluoropyridin-3-ylboronic acid (10.57 g, 75 mmol), and tetrakis(triphenylphosphine)palladium(0) (2.89 g, 2.5 mmol) was suspended in DME (300 mL) and aqueous sodium carbonate (10%) (50 mL, 100 mmol). The suspension was heated at reflux over night, cooled to r.t. and the reaction mixture was partitioned between EtOAc (300 mL) and NaHCO3 (aq., sat., 200 mL). The aqueous layer was washed with EtOAc twice. The organic layers were combined and washed with brine, then loaded on silica and purified via flash column (EtOAc:hexane=50-95%) on ISCO to give 4-(2-fluoropyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine as a light yellow solid with a green tint (1.85 g, 17% yield). MS (ESI, pos. ion) m/z: 214 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]4[CH3:34])=[C:24]([CH2:35][O:36][CH3:37])[CH:23]=3)[O:19][N:18]=2)[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8]C(C)(C)C)=[O:7].[ClH:38]>O1CCOCC1>[ClH:38].[F:1][C:2]1[CH:16]=[C:15]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]4[CH3:34])=[C:24]([CH2:35][O:36][CH3:37])[CH:23]=3)[O:19][N:18]=2)[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: COCc1cc(-c2nc(-c3ccc(OCC(=O)OC(C)(C)C)c(F)c3)no2)ccc1N1CCCCC1C
Agent: Cl
Solvent: C1COCCO1
Product: COCc1cc(-c2nc(-c3ccc(OCC(=O)O)c(F)c3)no2)ccc1N1CCCCC1C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Tert-butyl (2-fluoro-4-{5-[3-(methoxymethyl)-4-(2-methylpiperidin-1-yl)phenyl]-1,2,4-oxadiazol-3-yl}phenoxy)acetate (340 mg, 0.66 mmol) was dissolved in a 4M solution of HCl in dioxane (4 mL). The resulting mixture was stirred at RT for 15 hours. The precipitate was filtered off, washed with Et2O (3×) and pentane (3×), then dried under reduced pressure to give the title compound an as white powder (287 mg, 88%). 1HNMR (DMSO-d6, 300 MHz): 8.18 (brs, 1H), 8.07 (brs, 1H), 7.86 (m, 2H), 7.40 (brs, 1H), 7.30 (dd, J=8.6, 8.5 Hz, 1H), 4.91 (s, 2H), 4.58 (brs, 2H), 3.41 (s, 3H), 3.26 (m, 1H), 3.07 (m, 1H), 2.65 (m, 1H), 1.84-1.47 (m, 6H), 0.87 (brs, 3H). LC/MS (Method A): 456.3 (M+H)+; 454.4 (M−H)−. HPLC (Method A) Rt: 3.42 min (Purity: 99.7%).
Reaction SMILES: [CH2:1](Cl)[C:2](=[CH2:4])[CH3:3].[C:6]1([C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9])[OH:7]>>[CH2:1]([O:7][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[OH:9])[C:2](=[CH2:4])[CH3:3]
Reactant: Oc1ccccc1O
Reactant: C=C(C)CCl
Product: C=C(C)COc1ccccc1O
Yield: 68 %

Procedure:
These Examples A-D show that if the alkaline reagent used is sodium hydroxide or potassium hydroxide, an increase in the amount of methallyl chloride used improves the degree of conversion of the pyrocatechol as well as the yield of monoether, but results in a substantial formation of diether and of benzene ring alkylation products. Thus, if reference is made to Examples B and D, the use of one mol of methallyl chloride per mol of pyrocatechol, results in monoether/diether molar ratios of, respectively, 1.8 in Example B and 3.8 in Example D. If reference is now made to Examples 1 to 14 according to the present Patent Application, it will be seen that according to the process claimed, it is possible to use large amounts of methallyl chloride without reducing the selectivity of the reaction. Thus, according to Example 1, the use of 1.5 mols of methallyl chloride per mol of pyrocatechol makes it possible to achieve a molar ratio of monoether/diether of 7.6, whilst having a yield of 68% of o-methallyloxyphenol relative to the pyrocatechol starting material, and a content of benzene nucleus alkylation products of 4% relative to pyrocatechol converted.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[N:30]=[C:29](Cl)[N:28]=[CH:27][N:26]=1>CN(C=O)C>[Cl:24][C:25]1[N:30]=[CH:29][N:28]=[C:27]([N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)[N:26]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: FC(F)(F)c1ccc2c(c1)NCCC2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc2c(c1)N(c1ncnc(Cl)n1)CCC2
Temperature: 0 °C
Yield: 100 %

Procedure:
7-(Trifluoromethyl)-1,2,3,4-tetrahydroquinoline (440 mg, 2.2 mmol) was dissolved in DMF (10 mL) under N2 at room temperature. DIEA (284 mg, 2.2 mmol) was added, and the reaction solution was cooled to 0° C. 2,4-Dichloro-1,3,5-triazine was added, and reaction was stirred with gradual warming to RT. The reaction was quenched after 3 h with water, which caused a fine precipitate to form, which is not filterable. This mixture was extracted 3 times with EtOAc. The EtOAc extracts were then washed brine, combined, dried over Na2SO4, filtered, concentrated, and dried under high vacuum giving 1-(4-chloro-[1,3,5]triazin-2-yl)-7-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (800 mg (>100%)) of a yellow oil that was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C@@H:10]3[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12][CH2:11]3)[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.[CH:19]([C@@H:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:30]#[N:31])[CH:27]=2)[CH2:22]1)=O>>[F:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C@@H:10]3[CH2:11][CH2:12][C@H:13]([NH:16][CH2:19][C@@H:21]4[CH2:29][C:28]5[C:23](=[CH:24][CH:25]=[C:26]([C:30]#[N:31])[CH:27]=5)[CH2:22]4)[CH2:14][CH2:15]3)[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1
Reactant: N#Cc1ccc2c(c1)C[C@@H](C=O)C2
Reactant: Cc1nc2cc(F)ccc2n1[C@H]1CC[C@@H](N)CC1
Product: Cc1nc2cc(F)ccc2n1[C@H]1CC[C@@H](NC[C@H]2Cc3ccc(C#N)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of cis-4-(5-fluoro-2-methyl-benzoimidazol-1-yl)-cyclohexylamine and (S)-2-formyl-indan-5-carbonitrile through the same reductive amination method described previously. LC-MS showed a single peak, C25H27FN4 (m/e) calcd 402.2220, obsd 403.2 (M+H). 1H-NMR (CD3OD) □ 7.82 (q, 1H), 7.56 (s, 1H), 7.48 (d, 1H), 7.39 (d, 1H), 7.22 (d, 1H), 6.99 (t, 1H), 4.37 (m, 1H), 3.25 (m, 2H), 2.96 (br s, 1H), 2.65-2.90 (m, 7H), 2.61 (s, 3H), 1.99 (br d, 2H), 1.74 (m, 2H), 1.65 (br d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]5([CH2:31][CH2:30]5)[C:22]4=[O:32])[CH2:14][CH2:13]3)[C:11](=[O:33])[N:10]([CH2:34][C:35]3[CH:47]=[CH:46][CH:45]=[CH:44][C:36]=3[C:37]([O:39]C(C)(C)C)=[O:38])[CH2:9]2)=[CH:4][CH:3]=1.C(O)=O.C([SiH](CC)CC)C.Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH2:20][N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]5([CH2:30][CH2:31]5)[C:22]4=[O:32])[CH2:16][CH2:17]3)[C:11](=[O:33])[N:10]([CH2:34][C:35]3[CH:47]=[CH:46][CH:45]=[CH:44][C:36]=3[C:37]([OH:39])=[O:38])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccc(F)cc2)C2(CCN(CCCN3C(=O)C4(CC4)c4ccccc43)CC2)C1=O
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: C1COCCO1
Solvent: O=CO
Product: O=C(O)c1ccccc1CN1CN(c2ccc(F)cc2)C2(CCN(CCCN3C(=O)C4(CC4)c4ccccc43)CC2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To tert-butyl 2-((1-(4-fluorophenyl)-4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.12 g, 0.19 mmol) was added concentrated formic acid (2 mL) and triethylsilane (0.05 mL). After stirring at room temperature for 18 hours, the reaction mixture was concentrated, isolated by pTLC (10% methanol/dichloromethane) and lyophilized with 4M HCl in dioxane (0.5 mL) to obtain the title compound as a hydrochloride salt (0.038 g, 33%); 1H NMR (DMSO-d6): δ 1.53 (t, 2H, J=3.6 Hz), 1.61 (t, 2H, J=3.6 Hz), 2.00 (d, 2H, J=14.4 Hz), 2.08 (t, 2H, J=8 Hz), 2.70 (t, 2H, J=13.6 Hz), 3.20 (br, 2H), 3.45-3.72 (m, 4H), 3.83 (t, 2H, J=7.2 Hz), 4.64 (s, 2H), 4.91 (s, 2H), 6.99-7.10 (m, 6H), 7.20-7.28 (m, 2H), 7.31 (d, 1H, J=7.6 Hz), 7.42 (t, 1H, J=7.6 Hz), 7.59 (t, 1H, J=6.8 Hz), 7.91 (dd, 1H, J=7.6 and 1.2 Hz), 10.26 (br, 1H), 13.18 (s, 1H); MS for C34H35FN4O4 m/z 583.3 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:36]1[C:40]2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.Cl.CN>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:36][CH3:40])=[O:27])=[CH:24][C:23]=4[C:31]([F:32])([F:34])[F:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3C(F)(F)F)ncc21
Reactant: On1nnc2ccccc21
Agent: CN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)c(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 41.1 %

Procedure:
To a mixture of 0.125 g (0.257 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzoic acid (I-204) and 9 mL of dimethylformamide was added 0.0521 g (0.386 mmole) of 1-hydroxybenzotriazole, 0.146 g (0.385 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.140 g (1.081 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0260 g (0.385 mmole) of methylamine hydrochloride was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.0527 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-methyl-3-trifluoromethyl-benzamide (I-210) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH3:12])[S:4][C:3]=1[C:13]([NH2:15])=[O:14].O=[C:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.[O-]S([O-])(=O)=O.[Mg+2].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C([O-])(O)=O.[Na+]>CCCCCC.CO.CCOC(C)=O.CC(N(C)C)=O>[CH3:12][C:11]1[NH:10][N:9]=[CH:8][C:7]=1[C:5]1[S:4][C:3]2[C:13](=[O:14])[NH:15][C:17]3([CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]3)[NH:1][C:2]=2[CH:6]=1
Reactant: Cc1[nH]ncc1-c1cc(N)c(C(N)=O)s1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CCCCCC
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC1(CCC(NC(=O)OC(C)(C)C)CC1)N2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 3-amino-5-(5-methyl-1H-pyrazol-4-yl) thiophene-2-carboxamide (111 mg, 0.50 mmol), tert-butyl (4-oxocyclohexyl)carbamate (320 mg, 1.50 mmol), MgSO4 (120 mg, 1.00 mmol), CSA (11.6 mg, 0.05 mmol) and DMA (3 mL) was stirred at 100° C. for 1 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, hexane to EtOAc then to 80:20 EtOAc/MeOH). The residue obtained was dissolved with small amount of MeOH/EtOAc and added dropwise to a stirred solution of hexane (100 mL). The precipitate was collected by filtration to afford the title compound (122 mg, 58%, a mixture of 11:9 cis/trans isomers, absolute structure not determined) as yellow solid:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:5]2[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=2[N:7]=1.[CH:19]1([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[C:28]([F:41])[CH:27]=2)=[O:24])[CH2:21][CH2:20]1.ClCCl.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.CCO.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:19]1([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:2]3[N:3]=[C:4]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]4[CH3:18])[C:5]4[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=4[N:7]=3)=[C:28]([F:41])[CH:27]=2)=[O:24])[CH2:21][CH2:20]1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C)C2
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CN(C)C2
Temperature: 115 °C
Yield: 10.9 %

Procedure:
To a solution of (S)-4-(2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 12) (150 mg, 0.55 mmol) and 1-cyclopropyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 29) (212 mg, 0.69 mmol) in DME/EtOH/H2O (7/3/2) (2 mL) was added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (22 mg, 0.027 mmol) and Cs2CO3 (538 mg, 1.65 mmol). The reaction mixture was then heated by microwave at 115° C. for 45 min. The crude reaction mixture was partitioned between EtOAc (25 ml) and water (25 ml). The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo. Residue was then purified by preparative HPLC at low pH to afford a yellow solid (25 mg, 0.06 mmol, 11%).
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[NH2:11][C:12]1[S:13][C:14]([CH:20]=[O:21])=[C:15](Cl)[C:16]=1[C:17]#[N:18]>O>[NH2:11][C:12]1[S:13][C:14]([CH:20]=[O:21])=[C:15]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:16]=1[C:17]#[N:18]
Reactant: O=S([O-])c1ccccc1
Reactant: N#Cc1c(N)sc(C=O)c1Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1c(N)sc(C=O)c1S(=O)(=O)c1ccccc1
Reaction time: 8 h
Yield: 83 %

Procedure:
A solution of 82 parts of sodium phenylsulfinate in 500 parts of water is added to a mixture of 93.3 g of 2-amino-4-chloro-3-cyano-5-formylthiophene an 500 parts of methylglycol, and the reaction mixture is heated at the boil for 6 hours. Thereafter, the solution is filtered while hot and the filtrate is left to stand overnight. The precipitated product is then filtered off under suction, washed with water and dried. 121 parts (83% of theory) of 2-amino-3-cyano-5-formyl-4-phenylsulfonylthiophene are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:11][O:10]1.C(O)=[O:19]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[CH2:11][OH:10]
Reactant: O=CO
Reactant: Fc1ccc(C2(Cn3cncn3)CO2)c(F)c1
Product: OCC(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Heat a solution of 1-[[2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole (57 g) [prepared as described in Example 2(c) of British patent application No. 2,099,818A, published 15 Dec. 1982] in formic acid (500 mL) at reflux overnight. Remove the solvent in vacuo at 85°. Dilute the residue with ice water (1 liter) and basify carefully with 10% K2CO3 solution. Dilute with MeOH (500 mL) and heat on steam bath (1.5hr). Remove the MeOH in vacuo and extract the remaining aqueous solution with EtOAc (2×500 mL). Wash the EtOAc layer with H2O and dry it oyer MgSO4 and evaporate it to dryness to give 49.7 g of the title compound as a solid, m.p. 130°-132° C.
Reaction SMILES: [CH2:1]1[CH2:17][O:16][C:3]2([CH2:9][O:8][C:7]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])([CH3:10])[CH2:6][CH2:5][CH2:4]2)[O:2]1.N1C=CC=CC=1>C(Cl)Cl.N1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6].[O-2].[O-2].[O-2].[Cr+6]>[CH2:17]1[CH2:1][O:2][C:3]2([CH2:9][O:8][C:7]([CH3:10])([CH2:11][CH2:12][CH2:13][CH:14]=[O:15])[CH2:6][CH2:5][CH2:4]2)[O:16]1
Reactant: CC1(CCCCO)CCCC2(CO1)OCCO2
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(CCCC=O)CCCC2(CO1)OCCO2
Yield: 69.5 %

Procedure:
Dry celite (40 g) and 6,6-ethylenedioxy-2-(4'-hydroxybutyl)-2-methyloxepane (4.88 g, 0.0196 mol) in methylene chloride (100 ml) are added to a pyridine-chromium trioxide solution [prepared from pyridine (18.6 g, 0.0284 mol) and chromium trioxide (11.8 g, 0.118 mol)]in dry methylene chloride (500 ml) at 10° C. in a nitrogen atmosphere. After 5 hours the mixture is filtered and the celite is washed with methylene chloride (10×50 ml). The solvent is removed at reduced pressure. The residue is diluted with ether (200 ml), filtered and the ether is removed at reduced pressure. The crude product (4.7 g) is chromatographed on SilicAR CC-7 (100 g) in hexane. Elution with 20% ethyl acetate/hexane gives 6,6-ethylenedioxy-2-methyl-2-(4'-oxobutyl)-oxepane (14) as a clear colorless oil (3,3 g, 70%): ir (neat) 1725 cm-1 (CHO).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](I)[CH:3]=1.[C:12]1([Mg]Cl)[CH:17]=CC=C[CH:13]=1.C([Cu])#N.C(Br)C=C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH2:17][CH:12]=[CH2:13])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1I
Reactant: Cl[Mg]c1ccccc1
Agent: N#C[Cu]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To 4-fluoro-2-iodo-1-nitrobenzene (40.0 g, 150 mmol) in THF (200 mL) at −40° C. was added phenylmagnesium chloride (80.0 mL, 2M in THF, 161 mmol) dropwise. The reaction was stirred for 30 min followed by dropwise addition of CuCN.2LiCl (26.0 g, 150 mmol) in THF. The mixture was stirred an additional 30 min at which time allyl bromide (20.0 g, 161 mmol) was added. The reaction was stirred at −40° C. for 2 h followed by rt overnight. The reaction was quenched with saturated ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4) and concentrated. Purification by flash chromatography provided the title compound of step B (11.0 g, 60.7 mmol, 42%). 1H NMR (400 MHz, CDCl3) δ ppm 3.70 (d, J=6.4 Hz, 2H), 5.08-5.71 (m, 2H), 6.87-6.02 (m, 1H), 7.01-7.11 (m, 2H), 7.95-8.05 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1>C(O)C.C(O)(=O)C.[H][H].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1ccc(C(=O)CCCC(=O)O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(CCCCC(=O)O)cc1
Yield: 99.3 %

Procedure:
5-(4-methoxyphenyl)-5-oxopentanoic acid (8) (11.5 g) from the previous step was dissolved in ethyl alcohol (150 mL) and acetic acid (50 mL), 10% palladium-activated carbon (1.2 g) was added, then stirred overnight in hydrogen atmosphere at room temperature. After filtration and vacuum concentration, the above-identified compound was obtained as a colorless solid (10.7 g, yield 99%).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[C:12]([O:16][C:17](=[O:27])[NH:18][C:19]1[CH:24]=[N:23][C:22]([CH2:25]Br)=[CH:21][N:20]=1)([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([O:16][C:17](=[O:27])[NH:18][C:19]1[CH:24]=[N:23][C:22]([CH2:25][NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:21][N:20]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1cnc(CBr)cn1
Reactant: NC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc(CNC2CCC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
In a dried 100 mL round bottom flask was added cyclobutylamine (740 mg, 889 μL, 10.4 mmol, Eq: 3), K2CO3 (480 mg, 3.47 mmol, Eq: 1.00) and THF at rt. under argon. To the mixture was added a solution of (5-Bromomethyl-pyrazin-2-yl)-carbamic acid tert-butyl ester (1 g, 3.47 mmol, Eq: 1.00) in THF dropwise. The resulting reaction mixture was stirred vigorously at room temperature under argon overnight. The reaction was concentrated, diluted with water/DCM and extracted with DCM (2×30 mL). Combined organic extracts were concentrated to give a solid. The crude product was purified by LC chromatography (50 g spherical silica column) eluting with 5 to 10% MeOH in 1/1 EtOAc/Hex to afford 348 mg (36%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:12]2[C:13]([OH:15])=[O:14])=[O:10])=[CH:5][CH:4]=1.[N+](=[CH2:24])=[N-]>CO.O1CCCC1>[CH3:24][O:14][C:13](=[O:15])[C@@H:12]1[CH2:16][C@@H:17]([OH:19])[CH2:18][N:11]1[C:9]([O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=1)=[O:10]
Reactant: C=[N+]=[N-]
Reactant: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2C(=O)O)cc1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc(OC)cc1
Reaction time: 8 h

Procedure:
trans-1-(p-Methoxybenzyloxycarbonyl)-4-hydroxy-L-proline (5.0 g) was dissolved in 50 ml of methanol and 50 ml of tetrahydrofuran. An ethereal solution of diazomethane was added thereto under ice-cooling until nitrogen gas evolution stopped. The mixture was allowed to stand overnight and distilled to obtain trans-1-(p-methoxy-benzyloxycarbonyl)-4-hydroxy-L-proline methyl ester.