Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.C(=O)=O.CC(C)=O.C[Si](Cl)(C)C.C([O:25][B:26](OCC)[O:27]CC)C>C1COCC1>[Cl:10][C:4]1[CH:3]=[C:2]([B:26]([OH:27])[OH:25])[CH:7]=[C:6]([F:8])[C:5]=1[OH:9]
Reactant: CCOB(OCC)OCC
Reactant: Oc1c(F)cc(Br)cc1Cl
Agent: C[Si](C)(C)Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: OB(O)c1cc(F)c(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Bromo-2-chloro-6-fluoro-phenol (0.500 g, 2.21 mmol) is dissolved in dry THF, the reaction mixture is cooled to −78° C. (dry-ice/acetone bath) and 2.5M n-butylithium (1.06 ml, 2.66 mmol) is slowly added drop wise with stirring for 5 minutes. TMSCl (0.298 ml, 2.33 mmol) is added drop wise maintaining the temperature below −70° C. and the reaction mixture is stirred for 30 minutes. Boric acid triethyl ester is then added (0.385 ml, 2.26 mmol) followed by the second addition of n-butylitlium (1.06 ml, 2.66 mmol) maintaining the temperature below −65° C. The reaction mixture is stirred at −70° C. for 30 minutes then quenched with 5M HCl (5 ml) and allowed to warm to room temperature with stirring for 30 minutes. The reaction mixture is diluted with water and EtOAc and the organic portion is washed with 5M NaOH. The aqueous layer is acidified with 5M HCl and extracted with EtOAc, this organic portion is washed with brine, dried over MgSO4 and concentrated in vacuo to afford the title compound as an off white solid.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:39][C:40]3[CH:45]=[C:44]([CH3:46])[C:43]([OH:47])=[C:42]([CH3:48])[CH:41]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36]CC)=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[N:7]=[C:6]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:39][C:40]3[CH:41]=[C:42]([CH3:48])[C:43]([OH:47])=[C:44]([CH3:46])[CH:45]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[N:7]=[C:6]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[NH:5]1
Reactant: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(n4nc(-c5ccccc5)[nH]c4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.2 mg (0.05 mmol) LiOH in 2 mL water was added to a solution of 21 mg (0.03 mmol) (R)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate in 3 mL THF and the reaction mixture was stirred for 1 h at RT. The THF was evaporated down i.vac., the residue was acidified with 1 M HCl and again evaporated down i.vac. The residue was purified by HPLC, the fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:18])=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]#[N:34]>CC(C)=O>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:32][C:33]#[N:34])=[CH:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:18])=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#CCBr
Reactant: Cc1c(-c2ccccc2)n(C)c2cccc(-c3ccc(O)cc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(-c2ccccc2)n(C)c2cccc(-c3ccc(OCC#N)cc3)c12

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(1,3-dimethyl-2-phenyl-1H-indol-4-yl)-phenol (0.300 g, 0.957 mmol) was reacted with K2CO3 (0.159 g, 1.148 mmol) and bromoacetonitrile (0.134 g, 1.148 mmol) in acetone (5 ml) to give the product (0.311 g, 0.882 mmol, 92%) as a viscous oil. 1H NMR (DMSO-d6) δ 1.66 (s, 3H), 3.55 (s, 3H), 5.17 (s, 2H), 6.82 (dd, J=0.9, 7.2 Hz, 1H), 7.08 (d, J=8.9 Hz, 2H), 7.16 (t, J=7.2 Hz, 1H), 7.34-7.43 (m, 6H), 7.48 (t, J=7.0 Hz, 2H); [ESI(+)], m/z 353 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]3[C:23]4[S:29][CH:28]=[C:27]([C:30]5[CH:35]=[CH:34][C:33]([C:36]6[N:37]=[C:38]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:56])[C@@H:47]([NH:51][C:52]([O:54][CH3:55])=[O:53])[CH:48]([CH3:50])[CH3:49])[NH:39][CH:40]=6)=[CH:32][CH:31]=5)[C:24]=4[S:25][CH:26]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1)=O)(C)(C)C.[ClH:57]>CO.O1CCOCC1>[ClH:57].[CH3:55][O:54][C:52](=[O:53])[NH:51][C@H:47]([C:46]([N:42]1[CH2:43][CH2:44][CH2:45][C@H:41]1[C:38]1[NH:37][C:36]([C:33]2[CH:32]=[CH:31][C:30]([C:27]3[C:24]4[S:25][CH:26]=[C:22]([C:19]5[CH:20]=[CH:21][C:15]6[N:14]=[C:13]([C@@H:9]7[CH2:10][CH2:11][CH2:12][NH:8]7)[NH:17][C:16]=6[CH:18]=5)[C:23]=4[S:29][CH:28]=3)=[CH:35][CH:34]=2)=[CH:40][N:39]=1)=[O:56])[CH:48]([CH3:50])[CH3:49]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3csc4c(-c5ccc6nc([C@@H]7CCCN7C(=O)OC(C)(C)C)[nH]c6c5)csc34)cc2)c[nH]1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3csc4c(-c5ccc6nc([C@@H]7CCCN7)[nH]c6c5)csc34)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
Compound 68 (0.189 mmol) was dissolved in methanol (3.8 mL) and 4N HCl in dioxane (3.8 mL) was added. The mixture was stirred 1 hr at room temperature before concentration under reduced pressure. The residue was precipitated in diethyl ether to give compound E47 as a beige solid in 97% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 0.76 (d, 3H), 0.83 (d, 3H), 2.07-2.20 (m, 8H), 2.36 (m, 4H), 3.10-3.43 (m, 2H), 3.82 (m, 1H), 4.04 (m, 1H), 4.12 (t, 1H), 5.08 (m, 1H), 5.22 (t, 1H), 7.26 (d, 1H), 7.83 (m, 2H), 7.94 (m, 2H), 8.08-8.15 (m, 3H), 8.17 (m, 2H), 8.25 (s, 1H), 8.75 (s, 1H), 10.66 (s, 1H), 14.94 (s, 1H), 15.51 (s, 1H); MS (ESI, EI+) m/z=694.2 (MH+)
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:15]1)=[O:11])=O)(C)(C)C.Cl>CO.O1CCOCC1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:16]2[CH2:17][CH2:18][CH:14]([CH2:13][NH:12][C:10](=[O:11])[CH2:9][NH2:8])[CH2:15]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100.7 %

Procedure:
To a solution of 3-[{N-(tert-butoxycarbonyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (804 mg, 2.11 mmol) in methanol (10 mL) was added 4 N HCl in dioxane (5 mL). The solution was stirred at room temperature for 3.5 h. The reaction mixture was concentrated and 1 N NaOH solution (20 mL) was added. The mixture was extracted with dichloromethane (20 mL×3), and the combined extracts were dried over sodium sulfate and concentrated to give desired 1-(4-chlorobenzyl)-3-{(glycylamino)methyl)pyrrolidine (599 mg, 100%): The purity was determined by RPLC/MS (100%); ESI/MS m/e 282.2 (M++H, C14H20ClN3O).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:14]([S:30]([CH3:29])(=[O:32])=[O:31])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)[C@@H](c1ccccc1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of alcohol 4 (0.94 g, 3.18 mmol) and NEt3 (0.73 g, 7.18 mmol) at 0° C. in Cl2CH2 (10 mL), methanesulfonyl chloride (418 mg, 3.65 mmol) was added. The reaction mixture was allowed to stir at 0° C. for 45 min. It was then quenched with cold dilute HCl, diluted with Cl2CH2 and the organic layer was washed with an aqueous solution of NaHCO3 followed by brine and dried over Na2SO4. The solvent was eliminated in vacuo and the crude mesylate 6 was obtained as a foamy white solid which was used in the next step without further purification. 1H NMR (CDCl3).δ1.417 (s, 9H), 2.910 (s, 3H, CH3 --OMs), 3.705 (s, 3H, CH3O--), 4.853 (dd, J=9.6, 6.6 Hz, 1H, H--C2), 5.173 (bd, J=9.6 Hz, 1H, H--N), 5.893 (d, J=6.6 Hz, 1H, H--C3), 7.389-7.400 (m, 5H); IR (KBR) 3400, 2980, 2950, 1745, 1715, 1520, 1360, 1180 cm-1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([NH:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[CH:22][CH:23]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[N:20][C:21]([NH:24][CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])=[CH:22][CH:23]=2)=[CH:3][C:2]([C:35]2[CH:36]=[C:31]([Cl:30])[C:32]([OH:47])=[C:33]([Cl:46])[CH:34]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)CCNc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Product: CN(C)CCNc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cn1
Yield: 26.3 %

Procedure:
Following general procedure D, (6-bromo-4-(6-(2-(dimethylamino)ethylamino)pyridine-3-ylamino)quinolin-3-yl)(cyclopropyl)methanone (75 mg, 0.17 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (73 mg, 0.25 mmol) to afford the desired product (24 mg, 26%) as an orange solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.38 (s, 1H), 8.32-8.18 (m, 3H), 8.07 (d, J=9.3 Hz, 1H), 7.86 (dd, J=9.3, 2.6 Hz, 1H), 7.48 (s, 2H), 7.15 (d, J=9.3 Hz, 1H), 3.91 (t, J=6.1 Hz, 2H), 3.49 (t, J=6.1 Hz, 2H), 2.99 (s, 6H), 2.87-2.78 (m, 1H), 1.24-1.18 (m, 4H); ESI MS m/z 536 [C28H27Cl2N5O2+H]+; HPLC 96.5% (AUC), tR=11.28 min.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][S:12][C:13]3[NH:14][CH:15]=[C:16]([CH2:20][C:21]4[CH:22]=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=4)[C:17](=[O:19])[N:18]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:33][CH2:34]N(C(C)C)C(C)C.C(I)C>ClCCCl>[CH2:33]([N:14]1[CH:15]=[C:16]([CH2:20][C:21]2[CH:26]=[N:25][C:24]([O:27][CH3:28])=[N:23][CH:22]=2)[C:17](=[O:19])[N:18]=[C:13]1[S:12][CH2:11][C:10]1[CH:29]=[CH:30][C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:32][CH:31]=2)=[CH:8][CH:9]=1)[CH3:34]
Reactant: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCI
Solvent: ClCCCl
Product: CCn1cc(Cc2cnc(OC)nc2)c(=O)nc1SCc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 55 °C
Yield: 5.6 %

Procedure:
To a solution of 2-((4-(4-fluorophenoxy)benzyl)thio)-5-((2-methoxypyrimidin-5-yl)methyl)pyrimidin-4(1H)-one (167 mg, 0.371 mmol) in DCE (5 mL) was added Hunig's base (0.194 mL, 1.112 mmol) and EtI (0.045 mL, 0.556 mmol). The mixture was heated at 55° C. for 2 days. Purification via reverse phase flash chromatography then afforded the title compound (10 mg, 5.64% yield). LCMS: rt=3.24 min, [M+H+]=479
Reaction SMILES: [CH2:1]([C:10]([OH:12])=[O:11])/[C:2](/[C:7]([OH:9])=[O:8])=[CH:3]\[C:4]([OH:6])=[O:5].C(O)(=O)CCC(O)=[O:17]>>[C:4]([OH:6])(=[O:5])[CH2:3][C:2]([CH2:1][C:10]([OH:12])=[O:11])([C:7]([OH:9])=[O:8])[OH:17]
Reactant: O=C(O)CCC(=O)O
Reactant: O=C(O)/C=C(\CC(=O)O)C(=O)O
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O
Yield: 37.6 %

Procedure:
Trans-aconitic acid, 10.7 g (0.06 mole), is dissolved in 300 ml of water. An excess of strontium oxide, 12.5 g (0.121 mole) mole is added. This brings the pH to 12.4 and produces a mixture of the strontium salt of trans-aconitic acid and free strontium hydroxide. The resulting mixture is then stirred and heated for 3 hours in a Parr pressure reactor at a temperature of 200° C. The reaction mixture is then cooled and mixed with 121 g of 10% sulfuric acid solution. After stirring the mixture for about 10 minutes, it is filtered to remove precipitated SrSO4. The filtrate is then evaporated in vacuo to give a residue which is purified further by digesting with 100 ml acetone and refiltering to remove insolubles. The acetone filtrade is then evaporated to give an 8.8 g residue containing 54.3% (37.6% yield) of citric acid, 9.6% trans-aconitic acid, 4% succinic acid and the balance, mainly water.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.Cl.[S:9]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1)(=[O:12])(=[O:11])[NH2:10]>>[S:9]([C:13]1[CH:14]=[CH:15][C:16]([NH:19][N:20]=[CH:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:17][CH:18]=1)(=[O:12])(=[O:11])[NH2:10]
Reactant: O=Cc1ccco1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=Cc2ccco2)cc1

Procedure:
A solution of 2-furancarboxaldehyde (5 mmol) and 4-sulfamylphenylhydrazine hydrochloride is subjected to the General Procedure. The title compound is isolated as described in the general procedure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH:29]=[C:15]3[C:16]([NH:21][C:22]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=4)=[N:17][CH:18]=[C:19]([F:20])[C:14]3=[N:13]2)=[C:4]([CH:7]=[C:8]([CH:10]=C)[CH:9]=1)[C:5]#[N:6].I([O-])(=O)(=O)=[O:31].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[C:3]([N:12]2[CH:29]=[C:15]3[C:16]([NH:21][C:22]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=4)=[N:17][CH:18]=[C:19]([F:20])[C:14]3=[N:13]2)=[C:4]([CH:7]=[C:8]([CH:10]=[O:31])[CH:9]=1)[C:5]#[N:6]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(Cl)c(-n2cc3c(Nc4cc(C)ncn4)ncc(F)c3n2)c(C#N)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(C=O)cc4C#N)cc23)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
Osmium (VIII) oxide (2.5% wt in tert-butanol, 0.1 mL) was added to a solution of 3-chloro-2-[7-fluoro-4-(6-methylpyrimidin-4-ylamino)pyrazolo[4,3-c]pyridin-2-yl]-5-vinylbenzonitrile (42 mg, 0.1 mmol) in acetone (2.0 mL) and water (0.5 mL). Sodium periodate (47 mg, 0.22 mmol) was then added and the reaction mixture was stirred at room temperature overnight. The resultant mixture was partitioned between ethyl acetate and water and the layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (70-80% ethyl acetate in cyclohexane) to afford the title compound as a yellow glass (24 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.89 (s, 1H), 10.12 (s, 1H), 9.55 (d, J=2.5 Hz, 1H), 8.72-8.62 (m, 3H), 8.37 (s, 1H), 8.03 (d, J=3.4 Hz, 1H), 2.45 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].CN(C1C=CC=CN=1)C.[NH2:15][C:16]1[NH:17][CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:20]=1[C:21]([NH2:23])=[O:22]>O1CCCC1.O>[N+:30]([C:27]1[CH:26]=[CH:25][C:24]([C:19]2[C:20]([C:21]([NH2:23])=[O:22])=[C:16]([NH:15][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[NH:17][CH:18]=2)=[CH:29][CH:28]=1)([O-:32])=[O:31]
Reactant: CCN=C=O
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1N
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1[nH]cc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Reaction time: 16 h
Yield: 46.7 %

Procedure:
0.074 cm3 (0.891 mmol) of ethyl isocyanate and 0.005 mg (0.040 mmol) of dimethylaminopyridine are added, at a temperature close to 25° C., to a solution of 0.2 g (0.81 mmol) of 2-amino-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide in 15 cm3 of tetrahydrofuran. After stirring for 16 hours at a temperature close to 60° C., the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is stirred in 100 cm3 of water and then extracted with three times 50 cm3 of ethyl acetate. The organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is purified by flash chromatography [eluent: dichloromethane/methanol/acetonitrile (95/2.5/2.5 by volume)]. After concentrating the fractions under reduced pressure, 0.120 g of 4-(4-nitrophenyl)-2-(3-ethylureido)-1H-pyrrole-3-carboxamide is obtained in the form of a yellow powder. ES+: m/z=318 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].Cl[CH2:15][C:16]1[N:17]=[N:18][CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([C:3]1[N:4]([CH2:15][C:16]2[N:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:5]=[C:6]([C:11]([NH2:13])=[O:12])[C:7]=1[N+:8]([O-:10])=[O:9])[CH3:2]
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Reactant: ClCc1cccnn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1c([N+](=O)[O-])c(C(N)=O)nn1Cc1cccnn1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (15.7 g, 85.6 mmol, prepared using procedure in WO9849166), 3-(chloromethyl)pyridazine (11.0 g, 85.6 mmol, prepared using procedure in WO0023449) and cesium carbonate (27.8 g, 85.6 mmol) in N,N-dimethylformamide (200 ml) was stirred at 20° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between DCM (200 ml) and 10% aqueous Na2CO3 (100 ml). The phases were separated, and the aqueous layer extracted with further DCM (6×50 ml). The organic phases were combined, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (EtOAc/MeOH, 95:5-9010) to afford the title compound of preparation 43 (Note, the regioisomers were assigned on the basis of nOe experiments) (4.09 g, 14.8 mmol, 17%):
Reaction SMILES: S([O-])([O-])(=O)=O.[Ca+2].[CH3:7][C:8]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)([CH3:11])[CH2:9][OH:10].[C:21](=O)(O)[O-].[Na+].CI>CN(C)C(=O)C>[CH3:21][O:17][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([C:8]([CH3:7])([CH3:11])[CH2:9][OH:10])=[CH:20][CH:19]=1
Reactant: O=C([O-])O
Reactant: CC(C)(CO)c1ccc(C(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Agent: [Na+]
Solvent: CI
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(C(C)(C)CO)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
The following reagents were placed in a flask equipped with a magnetic stirrer, oil bath and reflux condenser protected with a guard tube containing anhydrous calcium sulfate ("Drierite"): p-(1,1-dimethyl-2-hydroxyethyl)benzoic acid, 20 g, 0.103 mole; sodium bicarbonate, 9.4 g, 0.112 mole; N,N-dimethylacetamide, 100 mL; and methyl iodide, 28.4 g, 0.2 mole. The mixture was heated at 80° C. for 2.5 hours, cooled to room temperature and filtered to remove any unreacted hydroxyacid. The clear solution was then poured into 600 mL water and stirred for 10 minutes. 50 mL of 5% aqueous sodium bicarbonate was added and the resultant solution extracted 3 times with 120 mL portions of ether. The ether layers were combined, washed with dilute aqueous bicarbonate, dilute aqueous sodium thiosulfate and finally water, and dried over anhydrous potassium carbonate. The ether solution was evaporated to give a colorless liquid which crystallized upon standing at room temperature. Yield 99%. The compound was purified by distillation, bp 135°- 140° C. at 0.3 to 0.5 mm Hg, (0.04 to 0.667 kPa) followed by recrystallization from ether/pentane (1/4 vol.) at -20° C., mp 44°-45° C. Elemental analysis, IR and NMR spectra were all consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[NH:9]2.[CH3:18]I>CCCCCC.CN(C=O)C>[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[N:9]2[CH3:18]
Reactant: COC(=O)c1cc2c(OC)cccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(OC)cccc2n1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
NaH (60% dispersion in mineral oil, 0.3 g, 7.3 mmole) was washed with hexane then suspended in anhydrous DMF (16 mL). The mixture was cooled to 0° C. and methyl 4-methoxy-1H-indol-2-carboxylate (1.0 g, 4.87 mmole) was added. The mixture was stirred under argon for 10 min, then MeI (13 mL, 20 mmole) was added, and the thick slurry was stirred at RT for 2.5 hr. The reaction was quenched with 10% NH4Cl (2 mL) and concentrated. The residue was partitioned between H2O and Et2O, and the organic layer was dried over MgSO4 and concentrated to yield the title compound (1.03 g, 96%) as a white solid: MS (ES) m/e 220.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[Br:13]Br>C(Cl)Cl>[Br:13][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:9][C:10]([OH:12])=[O:11]
Reactant: COc1cccc(CC(=O)O)c1
Reactant: BrBr
Solvent: ClCCl
Product: COc1ccc(Br)c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3-methoxyphenyl)acetic acid (4.50 g, 27.1 mmol) in DCM (25 ml), was added bromine (1.40 ml, 27.1 mmol) dropwise at 0° C. (ice-water bath). The mixture was stirred overnight at RT and quenched by addition of 5% sodium thiosulfate solution. The organic layer was washed with brine, dried with MgSO4 and concentrated under a stream of nitrogen to give the titled compound, 2-(2-bromo-5-methoxyphenyl)acetic acid as white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([CH2:13][CH2:14][CH2:15][C:16]([NH:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[O:17])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:3]=1.N1C=CC=CC=1.[CH3:41][C:42]([CH3:47])([CH3:46])[C:43](Cl)=[O:44]>>[O:21]([CH2:20][CH2:19][NH:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][C:5]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]([C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:3]=[C:2]([NH:1][C:43](=[O:44])[C:42]([CH3:47])([CH3:46])[CH3:41])[S:6]1)[Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)C(=O)N1N=C(N)SC1(CCCC(=O)NCCO[Si](C)(C)C(C)(C)C)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)NC1=NN(C(=O)C(C)(C)C)C(CCCC(=O)NCCO[Si](C)(C)C(C)(C)C)(c2ccccc2)S1
Yield: 85.2 %

Procedure:
In the same manner as that in Step 3 of Reference Example 20, from the optically active 4-[5-amino-3-(2,2-dimethylpropionyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl]-N-[2-(tert-butyldimethylsiloxy)ethyl]butanamide (0.0683 g, 0.135 mmol) obtained in Step 6 mentioned above, pyridine (131 μL, 1.62 mmol) and trimethylacetyl chloride (0.166 mL, 1.35 mmol), optically active N-[2-(tert-butyl-dimethylsiloxy)ethyl]-4-[3-(2,2-dimethylpropionyl)-5-(2,2-dimethylpropionylamino)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl]butanamide (68.0 mg, 83%) was obtained.