Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]1([NH2:25])[CH2:24][CH2:23]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>ClCCl>[CH:22]1([NH:25][C:11](=[O:13])[CH:10]([OH:14])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 114.8 %

Procedure:
To 3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutanoic acid (3 g, 10.16 mmol), cyclopropanamine (780 μL, 11.26 mmol) in dichloromethane (70 ml) at 5° C. EDC (2.4 g, 12.52 mmol), HOBt (1.9 g, 12.41 mmol) and Et3N (3 ml, 21.52 mmol) were added and the mixture stirred at room temperature for 48 h. After completion of reaction dichloromethane (100 ml) was added, the solution washed with water and brine, dried, filtered off with suction and concentrated to give 3.9 g of a brown oil which was purified further via chromatography on silica gel (eluent: CH2Cl2+5-30% (v/v) methanol). After evaporation of the combined product fractions 0.82 g of a pale oil were obtained; ESI-MS [M-Boc+H]±: 235.1.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH2:19]([C:23]1[O:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1)[CH2:20][CH2:21][CH3:22]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:28]([C:26]3[N:27]=[C:23]([CH2:19][CH2:20][CH2:21][CH3:22])[O:24][C:25]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:29])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: CCCCc1nc(C(=O)O)c(-c2ccccc2)o1
Product: CCCCc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)c(-c2ccccc2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-butyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.08 min; [M+H]+=433.69.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#N)[CH:6]=1.C(O)=[O:15]>[Ni]>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[O:15])[CH:6]=1
Reactant: O=CO
Reactant: COC(=O)Cc1cccc(C#N)c1
Agent: [Ni]
Product: COC(=O)Cc1cccc(C=O)c1
Temperature: 110 °C

Procedure:
A solution of (3-cyanophenyl)acetic acid methyl ester 47 (0.86 g, 4.9 mmol) in 88% formic acid (6 mL) is combined with Raney nickel alloy (0.48 g) and heated to reflux for 24 hours at 110° C. After cooling to room temperature, the alloy is removed by filtration over Celite. The filtrate is concentrated to ˜10% of the original volume and diluted with EtOAc (50 mL) and washed three times with water (20 mL). The organic layer is dried (MgSO4), filtered and concentrated to afford crude product, which is purified by silica gel chromatography using an EtOAc/hexane gradient to give (3-formylphenyl)-acetic acid methyl ester 48 as an oil: 1H-NMR (400 MHz, CDCl3) δ=9.97 (s, 1H), 7.40-7.52 (m, 4H), 3.68 (s, 3H), 3.67 (s, 2H). MS calculated for C10H11O3 (M+H+) 179.1, found 179.1.
Reaction SMILES: [N:1]#[C:2][NH2:3].CC(C)([O-])C.[K+].[F:10][C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=1[S:29][CH3:30])[CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25].BrN1C(=O)CCC1=O>CO>[F:10][C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=1[S:29]([CH3:30])=[N:1][C:2]#[N:3])[CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25]
Reactant: CSc1ccc(CN2C(=O)c3ccccc3C2=O)cc1F
Reactant: N#CN
Agent: CC(C)(C)[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Solvent: CO
Product: CS(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1F
Temperature: 25 °C

Procedure:
Cyanamide (350 mg, 8.20 mmol) and potassium tert-butoxide (860 mg, 7.60 mmol) are added to a solution of 2-(3-fluoro-4-methylsulfanyl-benzyl)-isoindole-1,3-dione (preparation 15a, 2.00 g, 6.31 mmol) in methanol (50 mL). N-Bromosuccinimide (1.70 g, 9.50 mmol) is added and the mixture is stirred at room temperature over night. All volatiles are removed under reduced pressure, and the residue is treated with dichloromethane (20 mL). The mixture is washed with saturated aqueous sodium chloride solution, dried over Na2SO4 and concentrated under reduced pressure. The residue is directly used in the next step without further purification. Yield: 1.61 g (60% of theory); ESI mass spectrum: [M+H]+=342; r.t. HPLC: 0.76 min (5-95AB).
Reaction SMILES: C[CH2:2][O-:3].[Na+].C(OCC)=O.[C:10]1([C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCO>[OH:17]/[C:16](/[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[C:18](/[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)\[CH:2]=[O:3]
Reactant: CC[O-]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: CCOC=O
Product: O=C/C(=C(\O)c1ccccc1)c1ccccc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
To a cooled solution of NaOEt (763 mg, 11.21 mmol) in EtOH (100 ml) was added ethyl formate (0.91 ml, 11.21 mmol) dropwise. The resulting mixture is allowed to stand for 3 hours at 0 to 5° C., and then deoxybenzoin (2 g, 10.19 mmol) was added. The mixture was stirred for 2 hours at 0 to 5° C. and then placed in the refrigerator for 4 days. After the mixture was stirred overnight at room temperature, it was poured into ice-water, and acidified, and extracted with CH2Cl2. The organic layer was washed with brine, and dried over MgSO4 anhydride, and concentrated in vacuo. The residue was purified by column chromatography (10% ethyl acetate in hexane) to give the title compound as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21]CC2C=CC=CC=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(O)cc1
Yield: 70.2 %

Procedure:
Product from step 1 (1.2 g, 3.13 mmol) in EtOH/THF (10 mL/25 mL) was treated with 10% Pd on carbon (1.0 g) over period of 16 h at rt under H2 balloon. Reaction mixture was filtered through Celite and concentrated under reduced pressure. The crude mixture was purified by silica gel flash chromatography (20% EtOAc/Hexane) to obtain the title product (645 mg, 70%).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[N+:16]([C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[CH:21][C:20]=1[CH2:27][C:28]([N:30]([CH3:49])[C@@H:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=2)CC[C@H:32]1[N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)=[O:29])([O-:18])=[O:17].[N+](C1C=C([Cl:59])C(Cl)=CC=1CC(O)=O)([O-])=O.N1C=CC=CC=1.Cl.O(CC)CC.Cl>>[N+:16]([C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[CH:21][C:20]=1[CH2:27][C:28]([N:30]([CH3:49])[C@@H:31]([C:40]1[CH:35]=[CH:36][CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=1)[CH2:32][N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)=[O:29])([O-:18])=[O:17].[ClH:59]
Reactant: CN(C(=O)Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-])[C@@H]1c2cc([N+](=O)[O-])ccc2CC[C@H]1N1CCCC1
Reactant: O=C(O)Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CN(C(=O)Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-])[C@H](CN1CCCC1)c1cccc([N+](=O)[O-])c1

Procedure:
This compound was prepared via the general DCC/pyr coupling procedure from 8 (0.3690 g, 1.4801 mmol), 2-nitro-4,5-dichlorophenylacetic acid (0.7301 g, 2.920 mmol), DCC(0.6213 g, 3.01 mmol), and pyridine (0.24 mL, 3.01 mmol). The crude product was converted to the HCl salt with Et2O—HCl without chromatography and crystallized from MeOH to yield 13 HCl.(0.3232 g, 42%): m.p. (HCl salt) 165° C. (dec); 1H NMR (HCl salt, DMSO-d6) δ2.0 (br s, 4H, —CH2CH2—), 2.93 (s, 3H, —NCH3), 3.1-4.3 (complex, 6H, 3 —CH2—), 4.4 (s, 2H, benzylic methylene), 6.2 (m, 1H, —CH—), 7.7-7.8 (m, 2H, aromatic), 7.9 (s, 1H, aromatic), 8.14 (s, 1H, aromatic), 8.27 (d, J=7.7 Hz, 1H, aromatic), 8.43 (s, 1H, aromatic). MS(FAB) m/z 481. Anal. (C, H, N) C21H22N4O5Cl2 .HCl.0.5MeOH.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][SH:6].[CH2:7](Cl)/[CH:8]=[C:9](/[CH2:11][CH2:12][CH2:13][C@@H:14]([CH2:16][CH2:17][CH2:18][C@@H:19]([CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH3:20])[CH3:15])\[CH3:10].O>O1CCCC1.C1OCCOCCOCCOCCOCCOC1>[CH3:10][C:9]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:8][CH2:7][S:6][CH2:5][CH2:4][NH2:3]
Reactant: NCCS
Reactant: C/C(=C\CCl)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=CCSCCN)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
Under an atmosphere of argon, sodium hydride (9.60 g, 240 mmol, 60% dispersion in mineral oil) was added to a solution of 2-aminoethanethiol (15.3 g, 200 mmol) in 200 ml of tetrahydrofuran and the mixture was stirred at 20° C. for 30 minutes. To the reaction mixture, 18-crown-6 (50 mg, 0.190 mmol) was added and then a solution of phytyl chloride (1-chloro-3,7,11,15-tetramethyl-2-hexadecaene) [55.0 g, 175 mmol, prepared as described in Item a) given above] in 200 ml of tetrahydrofuran was added in dropwise for an hour at below 10° C. After stirring at 20°-30° C. for 24 hours, water was added to the reaction mixture until forming did not occur. The solvent was evaporated in vacuo to dryness and the remaining residue was extracted with ethyl ether. The ether layer was washed twice with water and an aqueous solution saturated with sodium chloride, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to dryness. The remaining residue was chromatographed on silica gel, eluting with CH2Cl2 /MeOH (10:1) to afford 50.9 g (81.8%) of the desired compound, as a pale brown oil.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[C:10]([O:14][P:15]([CH:22](O)[C:23]1[CH:45]=[CH:44][C:26]([CH2:27][CH:28]([C:40]([O:42][CH3:43])=[O:41])[NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[CH:25][CH:24]=1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(Cl)(Cl)Cl.[Cl-].[Na+].O>[C:10]([O:14][P:15]([CH:22]([F:7])[C:23]1[CH:45]=[CH:44][C:26]([CH2:27][CH:28]([C:40]([O:42][CH3:43])=[O:41])[NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[CH:25][CH:24]=1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)C(Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)C(Cc1ccc(C(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 117 %

Procedure:
To DAST (0.15 mL, 1.1 mmol) in anhydrous CHCl3 (0.6 mL) at -78° C. was slowly added compound 9 (536 mg, 1.0 mmol) in CHCl3 (2.0 mL). After 10 minutes, the reaction mixture was warmed to ambient temperature and stirred (20 minutes). The mixture was slowly diluted with brine (10 mL) then extracted with CHCl3 (2×10 mL) and the combined extracts dried (MgSO4) and evaporated under reduced pressure to yield crude 20 (629 mg). Purification by silica gel chromatography afforded pure 20 as a syrup (295 mg, 55%).
Reaction SMILES: [Li+].[OH-].[NH2:3][C:4]([C:6]1[NH:10][C:9]([C:11]([O:13]C)=[O:12])=[C:8]([Cl:15])[CH:7]=1)=[O:5]>C1COCC1.CO>[NH2:3][C:4]([C:6]1[NH:10][C:9]([C:11]([OH:13])=[O:12])=[C:8]([Cl:15])[CH:7]=1)=[O:5]
Reactant: COC(=O)c1[nH]c(C(N)=O)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1cc(Cl)c(C(=O)O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
LiOH (1 N in water, 2 mL, 2 mmol) was added to a solution of methyl 5-(aminocarbonyl)-3-chloro-1H-pyrrole-2-carboxylate (0.0602 g, 0.297 mmol) in THF (2 mL) and methanol (2 mL) and the solution was stirred at RT overnight. The reaction mixture was evaporated to a residue and partitioned with EtOAc and 1 N HCl. The organic layer was separated, dried over MgSO4 and evaporated to a solid to afford the title compound (0.057 g, 77%) as a tan solid which was used with no further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.07 (br. s., 1H), 7.80 (br. s., 1H), 7.43 (br. s., 1H), 6.57-6.89 (m, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC=CC=1>[C:8]([C:2]1[NH:1][CH:5]=[C:4]([CH:6]=[O:7])[N:3]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=Cc1c[nH]c(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
Imidazole 4-carboxaldehyde, 96 mg (1 mmole), is treated with 278.5 mg (1 mmole) of trityl chloride in 25 ml of DMF containing 139 μl of triethylamine (1 mmole) overnight. The DMF is pumped off in vacuo and the residue, taken up in benzene, is washed with dilute aqueous NaHCO3 three times, then brine, then dried with K2CO3, filtered and evaporated to afford compound 3.I.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[CH3:21][N:22]1[CH2:29][CH2:28][CH:27]2[CH:23]1[CH2:24][NH:25][CH2:26]2>>[Cl:1][C:2]1[C:3]([N:25]2[CH2:24][CH:23]3[CH:27]([CH2:28][CH2:29][N:22]3[CH3:21])[CH2:26]2)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CN1CCC2CNCC21
Product: CN1CCC2CN(c3c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c3Cl)CC21

Procedure:
Thus, for example, 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid can be reacted with 2-methyl-2,7-diazabicyclo[3.3.0]octane to give 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(2-methyl-2,7-diazabicyclo[3.3.0]oct-7-yl)-4-oxo-3-quinolinecarboxylic acid, which has a high antibacterial activity.
Reaction SMILES: C(OC1C([N+]([O-])=O)=C(N)C2C(=CC=CC=2)[N:10]=1)C1C=CC=CC=1.C(OC1C([N+]([O-])=O)=C(Cl)C2C(=CC=CC=2)N=1)C1C=CC=CC=1.[O:45]1[CH2:50][CH2:49][CH:48]([C:51]([O:53]C)=O)[CH2:47][CH2:46]1.[OH-].[NH4+]>C(N(CC)CC)C.CO.ClCCl>[O:45]1[CH2:50][CH2:49][CH:48]([C:51]([NH2:10])=[O:53])[CH2:47][CH2:46]1
Reactant: COC(=O)C1CCOCC1
Reactant: Nc1c([N+](=O)[O-])c(OCc2ccccc2)nc2ccccc12
Agent: O=[N+]([O-])c1c(OCc2ccccc2)nc2ccccc2c1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: NC(=O)C1CCOCC1

Procedure:
In step (5) of Reaction Scheme I, a benzyloxy-4-chloro-3-nitroquinoline of Formula XIX is treated with an amine of Formula R1—NH2 to provide a benzyloxy-3-nitroquinolin-4-amine of Formula XX. The reaction is conveniently carried out by adding the amine of Formula R1—NH2 to a solution of the benzyloxy-4-chloro-3-nitroquinoline of Formula XIX in a suitable solvent such as dichloromethane or methanol in the presence of a tertiary amine such as triethylamine. The reaction can be carried out at ambient temperature or at an elevated temperature such as, for example, the reflux temperature of the solvent. The reaction product can be isolated using conventional methods. Several mines of Formula R1—NH2 are commercially available; others can be prepared by known synthetic methods. For example, methyl tetrahydro-2H-pyran-4-carboxylate treated with ammonium hydroxide to form tetrahydro-2H-pyran-4-carboxamide, which can then be reduced with lithium aluminum hydride to provide tetrahydro-2H-pyran-4-ylmethylamine.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH2:22]>>[O:1]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:22][CH2:21][C:20]([O:19][CH3:18])=[O:23])=[O:14])=[CH:15][CH:16]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)CN
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: COC(=O)CNC(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-oxo-piperidine-1-yl)-benzoic acid (which was obtained in Example 151) and glycine methyl ester hydrochloride according to the procedure of Example 154 as a gum; MS (ES) m/z: 291.3 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH:12]=[CH2:13])[CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([Li])[CH2:16][CH2:17]C.CN(C)P(N(C)C)(N(C)C)=O.ICCC>O1CCCC1>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH:12]=[CH2:13])[CH2:8][C:9]#[C:10][CH2:15][CH2:16][CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: C#CCN(CC=C)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCI
Product: C=CCN(CC#CCCC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of allyl-prop-2-ynyl-carbamic acid tert-butyl ester (prepared in the manner described by Boger et al., J. Am. Chem. Soc., 1996, 118, 2109; 1.95 g) in anhydrous tetrahydrofuran (10 mL) was stirred at 0° C. in a cooling bath and treated with n-butyllithium (1.6 M solution in hexane; 7.2 mL) during a 5 min period. After being stirred for an additional 5 min, the solution was treated sequentially with hexamethylphosphoramide (2 mL) and a solution of 1-iodopropane (1.71 mL) in tetrahydrofuran (2 mL). After 65 min, the cooling bath was removed and the mixture was allowed to warm to room temperature where it stirred for 80 min. At the conclusion of this period, saturated aqueous ammonium chloride was added, followed by water to dissolve the solids. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to yield a residue. The residue was purified by flash chromatography to provide a pale yellowish oil (1.67 g). MS (ES+) m/z 238.27 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([C:14]#[N:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]([O:20]C)(C)(C)[CH3:17]>C(OC=C)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([C:14]#[N:15])[C@H:11]([O:13][C:16](=[O:20])[CH3:17])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)C(C#N)C1
Reactant: COC(C)(C)C
Solvent: C=COC(C)=O
Product: CC(=O)O[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C#N
Temperature: 22 °C

Procedure:
79.1 To a solution of 17.1 g (98.2% GC purity) of trans, rac-3-cyano-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared according to C. Y. Hong et al. (Bioorganic Medicinal Chemistry Letters, 2003, 13, 4399), by D. J. Kim et al. (Journal of Medicinal Chemistry, 1997, 40, 3584) or by S. U. Hansen & M. Bols (Acta Chemica Scandinavica, 1997, 52, 1214)) in 765 ml of t-butylmethyl ether and 85 ml of vinyl acetate was added 21.3 g of Lipase AK (Amano Enzyme Inc.) and the suspension was stirred at 22° C. until ca. 54% conversion (as calculated from the ee-values of substrate and product according to C. J. Sih et al. (J. Am. Chem. Soc., 1982, 104, 7294)) was reached. The enzyme was filtered off, the filtrate evaporated in vacuo and the residual oil chromatographed on 400 g silicagel (0.040-0.063 mm; dichloromethane/diethyl ether 9:1→3:1) to give the formed optically enriched (S,S)-3-acetoxy-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (10.7 g; 84% ee, optically further enriched in example 60.2) and the retained (R,R)-3-cyano-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (6.9 g). Analytics: +EI-MS: 213.3 (M+H+); [α]D=+1.20° (c=1.00, CHCl3); 97.8% ee (GC on BGB-176; 30 m×0.25 mm; H2; 90 kPa; 130° C. to 200° C. with 2° C./min; inj. 200° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH:7]([CH3:9])[CH3:8])Cl)[CH3:2].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>C(#N)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH:7]([CH3:9])[CH3:8])[C:18]1[NH:17][CH:21]=[CH:20][N:19]=1)[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)C(Cl)(c1ccccc1)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)(c1ncc[nH]1)C(C)C

Procedure:
12 g (0.05 mole) phenyl-isopropyl-chloroacetic acid ethyl ester (b.p. 95°C./0.3 mm Hg) are heated with 10 g imidazole and 100 ml acetonitrile at boiling temperature for 18 hours. After distilling off the solvent in a vacuum, 50 ml of water are added and the mixture is extracted by shaking with methylene chloride. The methylene chloride is dried and distilled off in a vacuum. The phenyl-isopropyl-imidazolyl-acetic acid ethyl ester is thus obtained in the form of an oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.[Cl:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][N:11]=[C:10]2[N:20]([CH2:29][CH2:30]I)[N:21]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:9]=12>C(Cl)Cl>[Cl:7][C:8]1[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:12][N:11]=[C:10]2[N:20]([CH2:29][CH2:30][N:1]3[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]3)[N:21]=[C:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:9]=12
Reactant: O[C@@H]1CCNC1
Reactant: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CCI
Solvent: ClCCl
Product: O[C@@H]1CCN(CCn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)C1
Reaction time: 24 h
Yield: 16.9 %

Procedure:
A solution of (R)-3-pyrrolidinol (166 mg, 1.9 mmol) in CH2Cl2 (1.5 ml) was added to 4-chloro-1-(2-iodoethyl)-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine (example 74 step 1) (113 mg, 0.24 mmol) and the reaction stirred at ambient for 24 h. The resultant residue was purified using chromatography (silica gel, gradient 20 to 100% ethyl acetate/isohexane, then 0 to 100% ethyl acetate/acetone) followed by preparative HPLC to give Compound 83 as an orange solid (17 mg).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[C:5]1([N:11]2[C:15]([OH:16])=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[N:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.S(=O)(=O)(O)O.[OH-].[Na+]>O1CCOCC1>[C:5]1([N:11]2[C:15]([OH:16])=[CH:14][C:13]([C:17]([O:19][C:2]([CH3:3])([CH3:1])[CH3:4])=[O:18])=[N:12]2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1cc(O)n(-c2ccccc2)n1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1cc(O)n(-c2ccccc2)n1
Temperature: -78 °C
Reaction time: 6 h

Procedure:
To condensed isobutylene (1 ml) in a resealable glass tube was added 1-phenyl-3-carboxy-5-hydroxypyrazole (1 g; 4.9 mmol) in 30 ml of dioxane. The reaction mixture was cooled to -78° C. and 0.5 ml of conc. sulfuric acid was then added. The tube was sealed, stirred at room temperature for 6 hours, and cooled. The tube was opened, the mixture was neutralized and then basified (pH=12) with 2N NaOH solution, and extracted with ethyl acetate (3×). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 431 mg of 1-phenyl-3-(t-butyloxycarbonyl)-5-hydroxypyrazole as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CC.[NH:21]([C:29](OCC1C=CC=CC=1)=O)[C@H:22]([C:26]([OH:28])=[O:27])[CH:23]([CH3:25])C.[C:39](Cl)(=O)CCCCCCCCCCCCCCC>>[N:21]1([C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:19])[CH2:29][CH2:25][CH2:23][C@H:22]1[C:26]([O:28][CH3:39])=[O:27]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CCCCCCCCCCCCCCCC(=O)N1CCC[C@H]1C(=O)OC

Procedure:
Instead of oleoyl chloride in ((a), a) palmitoyl chloride was used to obtain (a') palmitoyl-Pro-OMe (SUAM 1135).