Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:18]O)[C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:8]=1.FC1C=CC(C(=C)C(OC)=O)=CC=1.[CH:33]([NH2:36])([CH3:35])[CH3:34]>C1COCC1.CCOCC.CCOC(C)=O>[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][NH:36][CH:33]([CH3:35])[CH3:34])[C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:8]=1
Reactant: COC(=O)C(CO)c1ccc(F)cc1
Reactant: CC(C)N
Agent: C=C(C(=O)OC)c1ccc(F)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C(CNC(C)C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.4 %

Procedure:
Methanesulfonyl chloride (1.230 mL, 15.89 mmol) and TEA (4.642 mL, 33.30 mmol) was added to a stirred solution of methyl 2-(4-fluorophenyl)-3-hydroxypropanoate (3 g, 15.14 mmol) in THF (150 mL) at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 days. The resulting suspension was diluted with Et2O (200 mL), filtered and concentrated in vacuo to give a colorless oil containing the intermediate compound, methyl 2-(4-fluorophenyl)acrylate. 1H NMR (CDCl3, 400 MHz) 7.39 (dd, J 8.4 and 5.4 Hz, 2H), 7.04 (app. t, J=8.6 Hz, 2H), 6.36 (s, 1H), 5.87 (s, 1H), 3.83 (s, 1H.) The methyl 2-(4-fluorophenyl)acrylate was taken up into THF (150 mL) and treated with isopropylamine (6.446 mL, 75.68 mmol). The reaction mixture was stirred at room temperature for 2 hours, diluted with EtOAc (200 mL), washed with saturated aqueous bicarbonate (100 mL), dried over Na2SO4 and concentrated in vacuo to give pure methyl 2-(4-fluorophenyl)-3-(isopropylamino)propanoate (3.6 g, 99.39% yield). LCMS (APCI+) [M+H]+ 240.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C:8]1[C:9]([CH3:17])=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12].C[N:19](C)C=O>ClCCl>[OH:7][C:8]1[C:9]([CH3:17])=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:19])=[O:12]
Reactant: CN(C)C=O
Reactant: Cc1c(O)cccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1c(O)cccc1C(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
Oxalyl chloride (4.19 ml, 48 mmol) was added to an ice-cold solution of 3-hydroxy-2-methylbenzoic acid (3.62 g, 24 mmol) in dichloromethane (30 mL). N,N-dimethylformamide (2 mL) was then added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was concentrated in vacuo three times from toluene. The residue was then suspended in tetrahydrofuran (10 mL), added to ice-cold 0.88 ammonia solution (10 mL) and stirred for 2.5 hours, allowing the temperature to rise to ambient. The reaction mixture was then extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo and the residue was concentrated in vacuo from acetone and triturated with diethyl ether to afford the title compound as a solid in 45% yield. LRMS APCI m/z 152 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([Cl:12])=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C(OC([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=O)(C)(C)C>>[ClH:12].[F:1][C:2]1[C:3]([Cl:12])=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: Fc1cc2ccoc2c(Br)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Cl
Product: Fc1cc2ccoc2c(N2CCNCC2)c1Cl

Procedure:
Beginning with 0.26 gm (1.06 mMol) 5-fluoro-6-chloro-7-bromobenzofuran and 0.22 gm (1.16 mMol) 1-tert-butoxycarbonylpiperazine, the title compound was prepared essentially as described in GENERAL PROCEDURE II.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:54][C:55]1[N:59]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[N:58]=[CH:57][C:56]=1[C:66](O)=[O:67]>CN(C=O)C.O>[O:14]=[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]1)[CH2:12][NH:11][C:66]([C:56]1[CH:57]=[N:58][N:59]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:55]=1[CH3:54])=[O:67]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 11.74 %

Procedure:
DIPEA (189 mg, 0.256 mL, 1.48 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (prepared by the method described above) (208 mg, 0.59 mmol) in DMF (2 mL). HOBT (80 mg, 0.59 mmol) and EDCI (114 mg, 0.59 mmol) were then added at room temperature. After 2 minutes, 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (100 mg, 0.49 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 29 mg (11.74% yield) 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 94.32%. 1H NMR (DMSO-d6): δ 8.24 (bs, 1H), 8.14 (s, 1H), 7.88-7.74 (m, 2H), 7.7-7.6 (m, 1H), 7.6-7.4 (m, 6H), 4.2-4.4 (d, 2H), 3.9-3.6 (m, 4H), 3.5-3.4 (m, 2H), 3.2-3.0 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12]Br.[CH3:14][Si:15]([CH3:31])([CH3:30])[CH2:16][CH2:17][O:18][CH2:19][N:20]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[CH2:22][C:21]1=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(=O)C>CN(C=O)C>[N+:9]([C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][CH:7]=1)[CH2:2][C:22]1([C:23]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:20]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:30])([CH3:14])[CH3:31])[C:21]1=[O:29])[CH2:12]2)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)c2cccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 1,2-bis(bromomethyl)-4-nitrobenzene (40.9 g, 132 mmol, described in Intermediate 2) and 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (31.5 g, 119 mmol, described in Intermediate 1) in DMF (2 L) was added cesium carbonate (129 g, 397 mmol), portionwise, over 5 min. After 18 h, acetic acid (7.6 mL) was added and the mixture was concentrated to a volume of about 500 mL, then partitioned between EtOAc (1.5 L) and H2O (1 L). The organic layer was washed with H2O (1 L), then brine (500 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=412 (M+1).
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH:16]([CH:18]([CH2:22][CH2:23][CH3:24])C([O-])=O)[O:15][C:14]=2[CH:25]=1)[CH2:3][CH2:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[OH-:26].[Li+].Cl.C1[CH2:33][O:32]CC1>O>[OH:1][CH:2]([C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH:16]([CH2:18][CH2:22][CH2:23][CH2:24][C:33]([OH:32])=[O:26])[O:15][C:14]=2[CH:25]=1)[CH2:3][CH2:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1
Reactant: [OH-]
Reactant: CCCC(C(=O)[O-])C1Oc2ccc(C(O)CCc3cccs3)cc2O1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Solvent: O
Product: O=C(O)CCCCC1Oc2ccc(C(O)CCc3cccs3)cc2O1
Temperature: 23 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
A mixture of (±)-methyl-5-[[6-(1-hydroxy-3-(2-thienyl)propyl-1,3-benzodioxolyl]pentanoate (Compound F. 35 mg, 0.093 mmol) and lithium hydroxide (0.37 mL of a 0.5N solution in H2O, 0.186 mmol) in THF (0.74 mL) was stirred at 23° C. for 16 hours. The mixture was acidified with 1N HCl and extracted with EtOAc. The organic portion was dried (MgSO4) filtered and concentrated in vacuo. Flash column chromatography (silica gel, 100% EtOAc) afforded 33.3 mg (99%) of the title compound. 1H NMR (300 MHz, CDCl3) δ 12.0 (brs, 1H), 7.14 (d, J=5. 1 Hz, 1H), 7.00 (s, 1H), 6.93 (dd, J=3.3, 5.1 Hz, 1H), 6.83 (d, J=3.3 Hz, 1H), 6.59 (s,1H), 5.91 (s, 2H), 4.87-4.92 (m, 1H), 2.97 (t, J=5.4 Hz, 2H), 2.43-2.47 (m,2H), 2.32 (t, J=6.9 Hz, 2H), 1.86-2.18 (m, 2H), 1.44-1.64 (m, 5H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:15].[O:16]=[C:17]1[N:21]([C:22]2[CH:23]=[CH:24][C:25]3[S:26][CH2:27][C:28](=[O:32])[NH:29][C:30]=3[N:31]=2)[CH2:20][C@@H:19]([CH2:33]OS(C)(=O)=O)[O:18]1>>[O:16]=[C:17]1[N:21]([C:22]2[CH:23]=[CH:24][C:25]3[S:26][CH2:27][C:28](=[O:32])[NH:29][C:30]=3[N:31]=2)[CH2:20][C@@H:19]([CH2:33][NH:1][CH2:2][CH2:3][N:4]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]2=[O:15])[O:18]1
Reactant: CS(=O)(=O)OC[C@@H]1CN(c2ccc3c(n2)NC(=O)CS3)C(=O)O1
Reactant: NCCn1c(=O)[nH]c2ccccc2c1=O
Product: O=C1CSc2ccc(N3C[C@@H](CNCCn4c(=O)[nH]c5ccccc5c4=O)OC3=O)nc2N1
Yield: 18 %

Procedure:
Starting from 3-(2-aminoethyl)-2,4(1H,3H)-quinazolinedione (prepared according to J. Med. Chem. (1992), 35(26), 4903-10) and methanesulfonic acid (S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl ester (prepared in analogy to its (R)-enantiomer, described in WO 2010/041194) and using Procedure F, the title compound was obtained as a yellow solid (21 mg; 18% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=4)=[CH:10]3)[C:6]=2[CH:24]=1.[CH:25]([N:28]1[CH2:33][CH2:32][CH:31]([SH:34])[CH2:30][CH2:29]1)([CH3:27])[CH3:26].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:21]([N:16]1[C:15]([C:9]2[N:8]=[C:7]3[N:11]([CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([S:34][CH:31]5[CH2:32][CH2:33][N:28]([CH:25]([CH3:27])[CH3:26])[CH2:29][CH2:30]5)=[CH:24][C:6]=43)[CH:10]=2)=[N:19][C:18]([CH3:20])=[N:17]1)([CH3:23])[CH3:22]
Reactant: CC(C)N1CCC(S)CC1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(C(C)C)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)C)CC4)ccc2OCC3)n(C(C)C)n1
Temperature: 120 °C
Yield: 57.8 %

Procedure:
A mixture of 9-bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (210 mg, 0.541 mmol), 1-isopropylpiperidine-4-thiol (129 mg, 0.812 mmol), Pd2(dba)3 (25 mg, 5 mol %), XantPhos (31 mg, 10 mol %) and DIPEA (380 μl, 2.16 mmol) in dioxane (5 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. The reaction mixture was then diluted with DCM (75 mL) and purified by column chromatography (Si-PCC, gradient 2-15% MeOH in DCM followed by C18, gradient 15-50% MeOH in 0.5% TFA/H2O). The product containing fractions were combined and concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The basic fractions were concentrated under reduced pressure affording 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-9-(1-isopropylpiperidin-4-ylsulfanyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a white solid/gum (146 mg, 58%). LCMS: RT 2.20 min [M+H]+ 467.0
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[CH2:17][CH:16]2[N:18](C([O:21][CH2:22][CH3:23])=O)[CH:13]([CH2:14][CH2:15]2)[CH2:12]1.[OH2:24].NN.[OH-:27].[K+].[OH2:29]>C(O)CO>[C:22]([OH:21])(=[O:29])[C:23]([OH:27])=[O:24].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[CH2:17][CH:16]2[NH:18][CH:13]([CH2:14][CH2:15]2)[CH2:12]1
Reactant: [OH-]
Reactant: CCOC(=O)N1C2CCC1CC(c1ccc3ccccc3c1)C2
Reactant: O
Agent: NN
Agent: [K+]
Solvent: OCCO
Product: O=C(O)C(=O)O
Product: c1ccc2cc(C3CC4CCC(C3)N4)ccc2c1
Temperature: 25 °C

Procedure:
A mixture of 2.64 gm (8.53 mMol) 3-(naphth-2-yl)-8-ethoxycarbonyl-8-azabicyclo[3.2.1]octane, 2.14 gm (42.7 mMol) hydrazine hydrate, and 2.87 gm (51.2 mMol) potassium hydroxide in 70 mL ethylene glycol was heated at reflux for 2 hours. The reaction mixture was allowed to cool gradually to room temperature, poured into water and extracted well with diethyl ether. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was treated with oxalic acid to provide the title compound.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:21][C:22]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:25]=[CH:24][C:23]=1[CH2:36][C:37](O)=[O:38])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O.O>[CH2:14]([O:21][C:22]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:25]=[CH:24][C:23]=1[CH2:36][C:37]([N:11]1[CH2:12][CH2:13][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)=[O:38])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.4 %

Procedure:
To a solution (20 ml) of 4-benzylpiperidine (423 mg) and 2,4-dibenzyloxyphenylacetic acid (700 mg) in N,N-dimethylformamide are added triethylamine (0.56 ml) and diethyl cyanophosphate (393 mg) and the mixture is stirred at room temperature for 15 minutes. Water is added and stirring carried out for 10 minutes, followed by extraction of the product with dichloromethane. The dichloromethane layer is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off. The residue is subjected to purification by silica gel column chromatography. 1-(2,4-Dibenzyloxyphenylacetyl)-4-benzylpiperidine (1.0 g) in the colorless oily form is obtained from a fraction eluted with dichloromethane-ethyl acetate mixture (8:1).
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH3:17])[C:4]=2[N:3]=1.[C:18]1([CH2:24][C:25]2[N:29]=[C:28]([CH2:30][CH2:31][CH2:32]O)[O:27][N:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.N1CCOCC1>C1COCC1.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:32][CH2:31][CH2:30][C:28]3[O:27][N:26]=[C:25]([CH2:24][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:29]=3)[C:6](=[O:15])[N:5]([CH2:16][CH3:17])[C:4]=2[N:3]=1
Reactant: OCCCc1nc(Cc2ccccc2)no1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CCn1c(=O)n(CCCc2nc(Cc3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.9 %

Procedure:
A solution of 8-chloro-3-ethyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (150 mg, 0.59 mmol) in anhydrous THF (4 ml) was treated with 3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-propanol (154 mg, 0.71 mmol) and triphenylphosphine (200 mg, 0.76 mmol). DBAD (162 mg, 0.71 mmol) was added in one portion and the mixture was left to stir at rt, under nitrogen for 18 h. The mixture was degassed by high vacuum then Pd(PPh3)4 (68 mg, 0.059 mmol) and morpholine (515 μl, 5.9 mmol) were added. The mixture was left to stir at rt, under nitrogen, for 3 h. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated by high vacuum. The crude material was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities, then with 2% AcOH/MeOH to elute the compound. The UV active fractions were combined and concentrated by high vacuum. The product was further purified by MDAP. The product fractions were combined and concentrated to give the title compound as a white solid (61 mg, 25%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[O:17]=[C:18]1[C:23](C(Cl)=O)=[CH:22][CH:21]=[C:20]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:19]1.[CH2:32]([N:34]1[C:46]2[CH:45]=[CH:44][C:43]([NH2:47])=[CH:42][C:41]=2[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH3:33]>>[CH2:32]([N:34]1[C:46]2[CH:45]=[CH:44][C:43]([NH:47][C:10]([C@@H:9]3[CH2:13][C:14](=[CH2:16])[CH2:15][N:8]3[C:6]([C:23]3[C:18](=[O:17])[O:19][C:20]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:21][CH:22]=3)=[O:7])=[O:12])=[CH:42][C:41]=2[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH3:33]
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: C=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)c2ccc(CCCCC)oc2=O)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 70% purity by LC/MS. MS(ESI+): m/z=512.4.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:6]1[C:7](OC)=[O:8])=[O:4].[NH3:15]>CO>[OH:14][C@@H:11]1[CH:6]2[C:7](=[O:8])[NH:15][CH2:2][C:3](=[O:4])[N:5]2[CH2:13][CH2:12]1
Reactant: N
Reactant: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)CCl
Solvent: CO
Product: O=C1NCC(=O)N2CC[C@H](O)C12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of methyl (3S)-1-(chloroacetyl)-3-hydroxy-L-prolinate (D69, 1.48 g, 6.7 mmol) in 10 ml of MeOH and 60 ml of a saturated solution of NH3 in MeOH was stirred for 48 h at rt. The solvent was evaporated under reduced pressure, to afford a solid. Analysis indicated this to be the title compound as a pair of diastereoisomers. After a short chromatography column (CHCl3/MeOH 8/2 as eluent) the title compound was isolated as a foamy solid (1 g). Yield 88%.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:15]([CH3:16])[C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.C(OCC)(=O)C>[CH3:16][N:15]1[C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:3][CH2:4]3)=[CH:12][CH:13]=[C:14]1[C:17]#[N:18]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)CCN2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)CCN2S(C)(=O)=O
Reaction time: 3 h
Yield: 33.2 %

Procedure:
5-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile hydrochloride (100 mg, 0.38 mmol) was dissolved in methylene chloride (5 mL) and triethylamine (0.17 mL, 1.14 mmol) was added. The mixture was treated with methanesulfonyl chloride (0.033 mL, 0.42 mmol) and stirred for 3 hours. The mixture was diluted with ethyl acetate, washed with water, 2N HCl, water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via Isco chromatography (the Redisep® column, silica, gradient 20-60% ethyl acetate in hexane) to afford 1-methyl-5-[1-(methylsulfonyl)-2,3-dihydro-1H-indol-5-yl]-1H-pyrrole-2-carbonitrile (38 mg). MS (ES) m/z 301.8; HPLC purity 100.0% at 210-370 nm, 8.8 min.; the Xterra® column RP18, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.[NH2:8][C:9]1[CH:14]=[N:13][C:12]([CH3:15])=[CH:11][N:10]=1.Cl[C:17]1[C:18]2[N:26]=[C:25](Cl)[CH:24]=[CH:23][C:19]=2[N:20]=[CH:21][N:22]=1>>[CH3:7][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[S:1][C:25]1[CH:24]=[CH:23][C:19]2[N:20]=[CH:21][N:22]=[C:17]([NH:8][C:9]3[CH:14]=[N:13][C:12]([CH3:15])=[CH:11][N:10]=3)[C:18]=2[N:26]=1
Reactant: Cc1cnc(N)cn1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: Cn1ccnc1S
Product: Cc1cnc(Nc2ncnc3ccc(Sc4nccn4C)nc23)cn1

Procedure:
The compound of Example 43 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 2-mercapto-1-methylimidazole, 2-amino-5-methylpyrazine and 4,6-dichloropyrido-[3,2-d]pyrimidine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:25][CH:24]=3)[CH:22]=2)([F:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:40]>C(Cl)Cl.O1CCOCC1>[ClH:40].[ClH:40].[CH2:36]([C:20]1[N:19]=[N:18][C:17]([O:16][CH2:15][C:11]2([F:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:22][C:21]=1[C:23]1[CH:24]=[CH:25][C:26]([O:29][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)=[CH:27][CH:28]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCc1nnc(OCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCc1nnc(OCC2(F)CCNCC2)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester (0.15 mmol, 85 mg) in DCM (1 mL) was added 4 N HCl in dioxane (1.5 mL) and the reaction was stirred for 30 min. The volatiles were removed in vacuo and the residue was triturated with anhydrous ethyl ether (2×3 mL) and dried under high vacuum to provide 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(4-fluoro-piperidin-4-ylmethoxy)-pyridazine dihydrochloride (0.078 g).
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.[H-].[Na+].C1(C)C=CC(S(O[CH2:31][CH:32]([F:34])[F:33])(=O)=O)=CC=1>CN(C=O)C>[F:33][CH:32]([F:34])[CH2:31][O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)F)cc1
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OCC(F)F
Yield: 84.7 %

Procedure:
The same operation as in Example (90a) was performed using tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate (4.6 g, 17.6 mmol), sodium hydride (55% content, 1 g, 22.9 mmol), 2,2-difluoroethyl p-toluenesulfonate (5 g, 21.6 mmol) and DMF (50 mL). The residue was purified by column chromatography (elution solvent: hexane/ethyl acetate=10/1, 4/1, 2/1) to obtain 4.85 g of the title compound as a colorless oily substance (85%).