Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.Br[C:22]1[CH:23]=[C:24]([CH:39]=[CH:40][C:41]=1[N:42]1[CH2:46][C@H:45]([OH:47])[C@@H:44]([OH:48])[CH2:43]1)[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([Cl:38])([F:37])[F:36])=[CH:30][CH:29]=1)=[O:26].C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO>[Cl:38][C:35]([F:36])([F:37])[O:34][C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:41]([N:42]3[CH2:43][C@H:44]([OH:48])[C@@H:45]([OH:47])[CH2:46]3)=[C:40]([C:11]3[NH:7][N:8]=[CH:9][CH:10]=3)[CH:39]=2)=[CH:33][CH:32]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(-c2ccn[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (126 mg, 0.451 mmol) and PdCl2(PPh3)2 (15.84 mg, 23 μmol) were added to a mixture of 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)benzamide (Stage 77.1, 110 mg, 0.226 mmol) and Na2CO3 (0.451 mL, 0.903 mmol) in DME (1.5 mL)/EtOH (0.3 mL) in a vial, which was sealed, purged with argon and the RM was subjected to MW irradiation at 125° C. for 30 min. The RM was filtered through Hyflo® and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 12 g, n-hexane/EtOAc from 20% to 100% EtOAc). The resulting intermediate was dissolved in DCM (2 mL), treated TFA (0.314 mL, 4.07 mmol) and stirred at RT for 2 h. The solvent was evaporated off under reduced pressure to give a residue which was treated with sat. aq. Na2CO3 and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative HPLC (Condition 10). Fractions containing pure product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure to give an aq. residue which was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 4 g, DCM/EtOH from 98:2 to 92:8) to give the title product as a white solid. HPLC (Condition 7) tR=6.105 min, UPLC-MS (Condition 8) tR=0.91 min, m/z=465.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.81 (d, J=10.56 Hz, 2H) 3.24-3.38 (m, 2H) 3.81-3.91 (m, 2H) 4.99 (br.s, 1H) 5.04 (br.s, 1H) 6.26-6.36 (m, 1H) 6.72-6.87 (m, 1H) 7.31 (d, J=8.99 Hz, 2H) 7.47-7.94 (m, 5H) 10.10 (s, 1H) 12.75-13.04 (m, 1H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9](Cl)=[O:10])[CH2:2]2.[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:14]1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][CH:13]([NH:12][C:9]([C@H:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:10])[CH2:14]2)=[CH:21][CH:22]=1
Reactant: O=C(Cl)C1CN2CCC1CC2
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: O=C(NC1CCN(CCc2ccc(F)cc2)C1)[C@@H]1CN2CCC1CC2

Procedure:
1-Azabicyclo[2.2.2]octane-3-carbonyl chloride and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-azabicyclo[2.2.2]octane-3-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:25]2[S:29][C:28]([C:30]3([O:34][CH2:35][O:36][CH3:37])[CH2:33][CH2:32][CH2:31]3)=[N:27][CH:26]=2)=[C:4]2[CH:10]=[C:9]([C:11]([O:13]C)=[O:12])[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:3]([C:25]2[S:29][C:28]([C:30]3([O:34][CH2:35][O:36][CH3:37])[CH2:33][CH2:32][CH2:31]3)=[N:27][CH:26]=2)=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(C(=O)OC)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(C(=O)O)cc34)s2)CCC1
Temperature: 75 °C

Procedure:
A suspension of Example 46A (0.134 g, 0.238 mmol) in methanol (2.5 mL) was treated with 2 M aqueous sodium hydroxide solution (0.714 mL, 1.19 mmol). The reaction was heated at 75° C. for 40 minutes, cooled to ambient temperature, and concentrated under reduced pressure. The residue was suspended in water (2 mL), and the pH adjusted to ˜4 with 1 N aqueous HCl solution. The suspension was filtered, and the solid collected was washed with water and dried in a vacuum oven at 60° C. to provide the title compound. ESI(+) m/z 393.9 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.[C:12]([C:14]1[CH:15]=[CH:16][C:17]([F:25])=[C:18]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH:19]=1)#[CH:13]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:13]#[C:12][C:14]2[CH:15]=[CH:16][C:17]([F:25])=[C:18]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH:19]=2)=[CH:6][CH:5]=1
Reactant: FC(F)Oc1ccc(I)cc1
Reactant: C#Cc1ccc(F)c(CCCC#N)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: N#CCCCc1cc(C#Cc2ccc(OC(F)F)cc2)ccc1F
Temperature: 65 °C
Yield: 90.3 %

Procedure:
To a solution of 1-Difluoromethoxy-4-iodo-benzene (0.21 g, 0.79 mmol) in DMF (3.5 ml) were added TEA (0.55 mL, 57.4 mmol) and 4-(5-Ethynyl-2-fluoro-phenyl)-butyronitrile (0.48 g, 0.79 mmol). The reaction was degassed by bubbling argon through it for 5 min and then dichlorbis(triphenylphospine)palladium (0.0.28 g, 0.04 mmol), and copper iodide (0.008 g, 0.57 mmol) were added simultaneously. The reaction mixture was heated at 65° C. for 15 min. cooled and quenched with 0.1 N HCl (10 ml). The aqueous layer was extracted with Et2O (3×10 ml). The combined organic extracts were washed with brine (25 ml), dried (MgSO4), and concentrated. The crude material was purified by silica gel chromatography (10-20% Ethyl acetate/Petroleum Ether) to afford the titled compound (0.235 g, 90%) as a brown oil that solidified on standing, and was identified by NMR and mass spectral analyses. MS (EI+): 329 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH:24]=[O:25])[C:21]([OH:26])=[C:20]([C:27]([O:29][CH3:30])=[O:28])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].B.[Na]>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][OH:25])[C:21]([OH:26])=[C:20]([C:27]([O:29][CH3:30])=[O:28])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3cc(C=O)c(O)c(C(=O)OC)c3)cs2)cc1OCC
Agent: B
Agent: [Na]
Solvent: CO
Product: CCOc1ccc(-c2nc(-c3cc(CO)c(O)c(C(=O)OC)c3)cs2)cc1OCC
Yield: 99.5 %

Procedure:
In 20 ml of methanol was suspended 300 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-formylphenyl)thiazole with stirring. Threto was added 26.5 mg of sodium boron hydride at 0° C. The mixture was stirred at room temperature for 1 hour. 26.5 mg of sodium boron hydride was further added, and the resulting mixture was stirred at the same temperature for 1 hour. The solvent was removed from the reaction mixture by distillation. To the residue were added 30 ml of dichloromethane and 15 ml of water, and phase separation was conducted. The organic layer was washed with 10 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent to obtain 300 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-hydroxymethylphenyl)-thiazole.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]([N:9]1[CH:13]=[C:12]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH:11]=[N:10]1)[CH2:6][C:7]#[N:8].[OH:23]O.C(#N)C>>[CH3:1][S:2]([CH2:3][CH2:4][CH:5]([N:9]1[CH:13]=[C:12]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH:11]=[N:10]1)[CH2:6][C:7]#[N:8])=[O:23]
Reactant: OO
Reactant: CSCCC(CC#N)n1cc(-c2ncnc3[nH]ccc23)cn1
Solvent: CC#N
Product: CS(=O)CCC(CC#N)n1cc(-c2ncnc3[nH]ccc23)cn1
Yield: 30.5 %

Procedure:
A solution of 5-(methylthio)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-pentanenitrile (0.065 g, 0.00021 mol) and hydrogen peroxide (0.022 mL, 0.00023 mol) in ACN (1 mL, 0.02 mol) was stirred overnight. The reaction was concentrated and purified by HPLC to give 21 mg of a solid. The solid was triturated with MTBE (1 mL)/DCM (10 drops). The solid was filtered and washed to give 13 mg of a white solid (20% yield) which was dried rt to 50° C. for 2 h.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[C:11]([CH3:14])([CH3:13])[CH3:12].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]=[C:22]=[O:23])[CH:16]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:22](=[O:23])[NH:21][C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)=[CH:4][C:3]=1[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C=Nc1cccnc1
Reactant: CC(C)(C)c1cc2c(cc1Cl)NCC2
Product: CC(C)(C)c1cc2c(cc1Cl)N(C(=O)Nc1cccnc1)CC2
Yield: 35 %

Procedure:
6-Chloro-5-tert-butylindoline (D56) (0.21 g, 1.01 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The product was recrystallised from ethanol/diethyl ether to give the title compound (0.12 g, 35%) as a white crystalline solid m.p.=200° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:21])[C@H:11]([NH2:20])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([NH:29][C@@H:30]([C:42](O)=[O:43])[CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(OC(C)(C)C)=O>>[C:35]([N:20]([C@@H:11]([CH:10]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[OH:21])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:42](=[O:43])[C@H:30]([NH2:29])[CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H](CCc1ccccc1)C(O)c1nc2ccccc2o1
Product: CC(C)(C)OC(=O)NCCC[C@@H](N)C(=O)N(C(=O)OC(C)(C)C)[C@H](CCc1ccccc1)C(O)c1nc2ccccc2o1
Yield: 240.3 %

Procedure:
(1R)-1-[(RS)-(2-benzoxazolyl)hydroxymethyl]-3-phenylpropylamine (62 mg) is coupled with N,N′-bis-Boc-D-ornithine (51 mg) to afford the title compound (110 mg) as a glassy solid: 1H NMR (400 MHz, CDCl3, 3:2 mixture of diastereomers) δ 1.39-1.42 (2s, 18H), 1.58 (m, 3H), 1.86 (m, 2H), 2.09 (m, 1H), 2.67-2.78 (m, 1.6H), 2.92 (m, 0.4H), 2.96-3.22 (m, 2H), 4.07 (m, 0.4H), 4.18 (m, 0.6H), 4.59 (m, 1.4H), 4.78 (m, 0.6H), 5.04 (s, 1H), 5.14 (bd, 0.4H, NH), 5.26 (bd, 0.6H, NH), 7.09-7.37 (m, 7H), 7.50 (m, 1H), and 7.71 (m, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=[O:3].CS(C)=O.[C:11]([C:18]([CH3:23])([CH3:22])[CH:19]([NH2:21])O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C.P([O-])(O)(O)=O.[Na+]>C(Cl)Cl>[C:11]([C:18]([CH3:23])([CH2:19][NH2:21])[CH:22]=[O:3])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)C(C)(C)C(N)O
Reactant: O=C(Cl)C(=O)Cl
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C=O)CN
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
A solution of oxalyl chloride (15.24 g, 120 mmol) in 200 mL of MeCl2 was stirred and cooled to −60° C. followed by the drop wise addition of dimethylsulfoxide (19.7 g, 252 mmol) in 60 mL of MeCl2. After 10 min, a solution of 2-Boc-amino-2-methyl-1-propanol (18.9 g, 100 mmol) in MeCl2 (60 mL) was added drop wise at −70° C. The reaction mixture was allowed to warm to −40° C. for 10 min followed by cooling to −70° C. before the addition of a solution of triethylamine (28.28 g, 280 mmol) in MeCl2 (60 mL). The reaction mixture was allowed to warm to room temperature over a two-hour period and 40 mL of saturated sodium dihydrogen phosphate was added. The organic layer was washed with brine and dried over MgSO4. The solvent was removed to yield 17.3 g of 2-Boc-amino-2-methylpropionaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:13]=1[NH2:14]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[NH:14][C:13]3[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:12]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(O)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2nc(-c3ccc(Cl)cc3)[nH]c2c1
Yield: 87 %

Procedure:
Prepared from 4-chlorobenzoic acid (17.83 g, 0.114 mol) and 2-amino-5-nitroaniline (18 g, 0.114 mol), in a manner similar to that of Example 9b. Yield: 87%; Rf (6/4 toluene/ethyl acetate): 0.61; m.p.: 302.5-305° C.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]1[CH2:13][CH2:14][C:15](=[O:16])[C:7]1=[C:6]2[C:17]1[CH:30]=[CH:29][C:20]([CH2:21][N:22]2[C:26](=[O:27])[CH:25]=[CH:24][C:23]2=[O:28])=[CH:19][CH:18]=1.[CH2:32]([O:34][C:35](=[O:47])[C@H:36]([CH2:45][SH:46])[NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH3:33]>C(Cl)Cl.CO>[C:41]([O:40][C:38]([NH:37][CH:36]([CH2:45][S:46][CH:25]1[CH2:24][C:23](=[O:28])[N:22]([CH2:21][C:20]2[CH:29]=[CH:30][C:17]([C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:31])[CH3:1])[CH:4]=4)[CH:9]=[C:8]4[CH2:13][CH2:14][C:15](=[O:16])[C:7]=34)=[CH:18][CH:19]=2)[C:26]1=[O:27])[C:35]([O:34][CH2:32][CH3:33])=[O:47])=[O:39])([CH3:43])([CH3:44])[CH3:42]
Reactant: CN(C)c1ccc2cc3c(c(-c4ccc(CN5C(=O)C=CC5=O)cc4)c2c1)C(=O)CC3
Reactant: CCOC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C(CSC1CC(=O)N(Cc2ccc(-c3c4c(cc5ccc(N(C)C)cc35)CCC4=O)cc2)C1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.6 %

Procedure:
An oven-dried 25 mL one-necked round-bottomed flask equipped with a septum and a stir bar was charged with compound 17 (0.006 g, 0.015 mmol) in CH2Cl2/MeOH 1:1 (5 mL). N-Boc-L-cysteine ethyl ester (0.0036 g, 0.015 mmol) was added in one portion and the mixture mas stirred at rt for 10 min. The consumption of the starting material was monitored by TLC (AcOEt/n-hexane 1:1). The solution was then concentrated under reduced pressure and the reaction residue was purified by silica gel flash column chromatography, eluting with AcOEt/n-hexane 1:1, to provide 0.006 g of the title compound as a 1:1 mixture of two inseparable diastereomers (d1 and d2) in a 60% yield.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:20][CH2:19][CH2:18][C:17](=[N:21][OH:22])[CH:16]=1>CO>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:20][CH2:19][CH2:18][C:17](=[N:21][OH:22])[CH:16]=1
Reactant: COCOc1ccc(C2=CC(=NO)CCC2)c(OCOC)c1
Solvent: CO
Product: ON=C1C=C(c2ccc(O)cc2O)CCC1
Reaction time: 4 h
Yield: 81.3 %

Procedure:
3-[2,4-Bis(methoxymethoxy)phenyl]-2-cyclohexen-1-one oxime (0.1 g) was heated to 50° C. in methanol (5 ml) containing acidic ion exchange resin (0.3 g). After 4 hr, the mixture was filtered and the resin was washed with ammonia solution (50 ml). Filtrate and washings were combined, evaporated in vacuo and purified by flash column chromatography (SiO2, ethyl acetate/petroleum ether, 3:2, v/v) to furnish the title compound as a yellow solid (0.058 g, 81%). δH (DMSO) (mixture of stereoisomers) 1.68 (2H, m, major), 1.76 (2H, m, minor), 2.26 (2H, m, minor), 2.40-2.54 (4H major+2H minor, overlapping m), 6.15-6.30 (3H major+2H minor, overlapping m), 6.85-6.95 (1H major+2H minor, overlapping m), 9.26 (1H, bs, major), 9.32 (1H, bs, minor), 9.35 (1H, bs, major), 9.40 (1H, bs, minor), 10.17 (1H, s, minor), 10.49(1H, s, major); m/z (ES−) 437 (2M−H)−.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][C@H:8]([N:11]3C(=O)C4=CC=CC=C4C3=O)[CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1>CCO>[N:1]1([C@H:6]2[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](n2cccn2)C1
Solvent: CCO
Product: N[C@H]1CC[C@H](n2cccn2)C1
Yield: 64.5 %

Procedure:
A mixture of trans-N-[3-(1H-pyrazol-1-yl)cyclopentyl]phthalimide (R) (1.49 g, 5.30 mmol), and hydrazinemonohydorate (0.51 mL, 10.5 mmol) in EtOH (30 mL) was stirred at reflux for 3 h. After cooling, the reaction mixture was filtered followed by the removal of solvent. The crude product was purified by column chromatography (Chromatrex, CH2Cl2/EtOH=30/1) to yield trans-3-(1H-pyrazol-1-yl)cyclopentylamine (517 mg, 65%) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:30]=[CH:29][C:17]([O:18][CH:19]([F:28])[C:20]([NH:22][CH2:23][C:24]([O:26]C)=[O:25])=[O:21])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH:19]([F:28])[C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])=[CH:29][CH:30]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CNC(=O)C(F)Oc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CNC(=O)C(F)Oc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Reaction time: 3 h
Yield: 92.7 %

Procedure:
623 mg of methyl {4-[2-(4-chlorophenyl)sulfonylaminoethyl]-2-fluorophenoxyacetylamino}acetate are dissolved in 8 ml of methanol, and 2.8 ml of an aqueous 1N sodium hydroxide solution are added thereto. After the mixture is allowed to stand for 3 hours, the mixture is made acidic with 10% hydrochloric acid, extracted with ethyl acetate, dried and evaporated to remove the solvent. The residue is recrystallized from a mixture of tetrahydrofuran, isoproylether and n-hexane. 560 mg of {4-[2-(4-chlorophenyl)sulfonylaminoethyl]-2-fluorophenoxyacetylamino}acetic acid are obtained as colorless prisms.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[CH:37][C:6]([C:7]([NH:9][C:10]2[C:14]3[N:15]=[C:16]([C:18](=[O:29])[NH:19][C:20]([CH3:28])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:21])[S:17][C:13]=3[N:12](C(OC(C)(C)C)=O)[N:11]=2)=[O:8])=[CH:5][CH:4]=1.Cl.[Cl-].[Na+]>C(O)C.O1CCOCC1>[CH3:28][C:20]([NH:19][C:18]([C:16]1[S:17][C:13]2[NH:12][N:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:38][CH:37]=3)[C:14]=2[N:15]=1)=[O:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21]
Reactant: COc1ccc(C(=O)Nc2nn(C(=O)OC(C)(C)C)c3sc(C(=O)NC(C)(C)c4ccccc4)nc23)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(C(=O)Nc2n[nH]c3sc(C(=O)NC(C)(C)c4ccccc4)nc23)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.3 %

Procedure:
0.16 g (0.31 mmol) of tert-butyl 3-(4-methoxybenzoylamino)-5-(1-methyl-1-phenylethylcarbamoyl)-1H-pyrazolo[4,3-d]thiazole-1-carboxylate dissolved in 7 ml of ethanol is placed in a 100 ml round-bottomed flask. 1.5 ml (6.0 mmol) of a 4M solution of hydrochloric acid in dioxane are then added and the reaction mixture is stirred for 15 hours at 25° C. A further 1.5 ml (6.0 mmol) of 4M solution of hydrochloric acid in dioxane are added and the mixture is stirred for 15 hours at 25° C. The reaction medium is then concentrated to dryness under reduced pressure (40° C.) and the residue is taken up in 30 ml of dichloromethane and 30 ml of water, and basified with 0.1N sodium hydroxide solution. The emulsion obtained is resorbed by saturation with sodium chloride. After separation of the phases by settling, the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure (40° C.). The residue is purified by flash chromatography (msilica=30 g; eluent: 95/5 dichloromethane/methanol). 0.103 g of N-(1-methyl-1-phenylethyl)-3-(4-methoxybenzoylamino)-1-H-pyrazolo[4,3-d]thiazole-5-carboxamide is thus obtained in the form of a cream-coloured foam. m.p.K=226° C. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.70 (s, 6H); 3.86 (s, 3H); 7.09 (d, J=8.5 Hz, 2H); 7.20 (t, J=7.5 Hz, 1H); 7.30 (t, J=7.5 Hz, 2H); 7.41 (d, J=7.5 Hz, 2H); 8.07 (d, J=8.5 Hz, 2H); 8.53 (broad s, 1H); from 10.0 to 15.0 (very broad m, 2H).
Reaction SMILES: O[CH:2]=[C:3]([C:8]1[N:9]([CH3:17])[CH:10]=[CH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14])[C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[NH4+:22]>CO>[NH2:22]/[CH:2]=[C:3](/[C:8]1[N:9]([CH3:17])[CH:10]=[CH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14])\[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(=CO)c1c(C(=O)OC)ccn1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: COC(=O)/C(=C\N)c1c(C(=O)OC)ccn1C
Yield: 89.9 %

Procedure:
A solution of methyl 2-{2-hydroxy-1-[(methyloxy)carbonyl]ethenyl}-1-methyl-1H-pyrrole-3-carboxylate (65.2 g) and ammonium acetate (105 g) in methanol (800 ml) was heated at reflux for 7 hours. The reaction was cooled and the methanol removed. The residue was partitioned between ethyl acetate and water. Large amounts (>2 L) of ethyl acetate were used to dissolve the residue. The organic solution washed with water, dried (MgSO4) and the solvent removed to yield the title compound as a brown solid (58.4 g).
Reaction SMILES: [CH2:1]([CH:8]([N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23])[CH:9]([OH:12])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(OCC)(=O)C>[O:23]=[C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[N:13]1[C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]([OH:12])[CH2:10][O:11][S:31]([CH3:30])(=[O:33])=[O:32]
Reactant: O=C1c2ccccc2C(=O)N1C(Cc1ccccc1)C(O)CO
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@@H](O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
A solution of 0.51 g of an 83:17 mixture of the (1S,2S) and (1S,2R) isomers of 2-(1-benzyl-2,3-dihydroxypropyl)-2,3-dihydro-1H-isoindole-1,3-dione, 0.4 ml of pyridine and 1 ml of ethyl acetate is treated with 0.15 ml of methanesulfonyl chloride and the mixture is stirred at room temperature for 4 hours. The mixture is diluted with ethyl acetate and washed with 2% hydrochloric acid, and the extracts are dried and filtered. The filtrate is evaporated and the residue is purified on silica gel with methylene chloride/isopropanol (100:1). After evaporation and drying there is obtained 0.28 g (43%) of pure methanesulfonic acid (2S,3S)-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-2-hydroxy-4-phenylbutyl ester, NMR (CDCl3): 7.7 (m,4H); 7.1 (m,5H); 4.6 (m,2H); 4.3 (m,2H); 3.55 (d,J=7,1H); 3.3 (m,2H); 3.1 (s,3H).