Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](C(C)=O)[CH:2](C)C.[CH2:8]([N:10]([CH2:18][CH3:19])[C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)[CH3:9].C(=O)([O-])[O-].[K+].[K+].C(Br)C>O>[CH2:18]([N:10]([CH2:8][CH3:9])[C:11]1[CH:12]=[C:13]([O:17][CH2:1][CH3:2])[CH:14]=[CH:15][CH:16]=1)[CH3:19]
Reactant: CCN(CC)c1cccc(O)c1
Reactant: CC(=O)CC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCBr
Product: CCOc1cccc(N(CC)CC)c1
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A 1 liter reactor is charged with 150 ml of methyl isobutyl ketone, 73.1 g of 3-diethylaminophenol and 153.3 g of ground potassium carbonate. The mixture is stirred for 30 minutes, then 72.7 g of ethyl bromide are added and the autoclave is closed. The reaction mixture is heated first for 3 hours to 115°-129° C. and then for a further 5 hours at 140°-142° C. (pressure: 4 bar). After cooling to c. 25° C. and addition of water, the product is isolated with the organic phase, which is washed with water and concentrated by evaporation, to give 80.67 g (97.2% yield) of 3-diethylaminophenetol with a titre of 94.8%.
Reaction SMILES: [N+](C1C=CC=CC=1C[C:7](=O)[C:8]([O-:10])=[O:9])([O-])=O.O.[N+](C1C=CC=CC=1COC(N[C@H:27]1[C@H:30](CCOC(=O)C)[NH:29][C:28]1=[O:37])=O)([O-])=O.[CH:42]1C=CC=C[CH:43]=1>>[C:8]([O:10][CH2:42][CH2:43][N:29]1[CH2:30][CH2:27][C:28]1=[O:37])(=[O:9])[CH3:7]
Reactant: CC(=O)OCC[C@@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1[N+](=O)[O-]
Reactant: O=C([O-])C(=O)Cc1ccccc1[N+](=O)[O-]
Reactant: c1ccccc1
Solvent: O
Product: CC(=O)OCCN1CCC1=O

Procedure:
The o-nitrobenzylglyoxylate, from Step B, is dissolved in 100 ml of benzene and refluxed using a Dean-Stark water separator containing 5 g of CaH2 for 0.5 hr; trans-3-[o-nitrobenzyloxycarbonylamino]-4-[2-acetoxyethyl]-2-azetidinone (3.51 g) is added and the mixture is refluxed for 6 hours, cooled and evaporated. The residue is chromatographed to give trans-1-(o-nitrobenzyloxycarbonylhydroxymethyl)-3-(o-nitrobenzyloxycarbonylamino)-4-(2-acetoxyethyl-2-azetidinone (3.8 g).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:9]([NH:11][CH2:12][C:13]([NH:15][C@H:16]([C:24]([NH:26][NH:27][C:28]([CH3:30])=[O:29])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])=[O:10])[CH2:3][CH2:4][S:5]([CH3:8])(=[O:7])=[O:6].[CH3:38][C:39]([O:42][C:43]([NH:45][C@H:46]([C:55]([O:57]CC1C=CC([N+]([O-])=O)=CC=1)=O)[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=1)=[O:44])([CH3:41])[CH3:40]>>[NH:45]([C:43]([O:42][C:39]([CH3:38])([CH3:40])[CH3:41])=[O:44])[C@H:46]([C:55]([NH:1][C@@H:2]([C:9]([NH:11][CH2:12][C:13]([NH:15][C@H:16]([C:24]([NH:26][NH:27][C:28]([CH3:30])=[O:29])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])=[O:10])[CH2:3][CH2:4][S:5]([CH3:8])(=[O:7])=[O:6])=[O:57])[CH2:47][C:48]1[CH:49]=[CH:50][C:51]([OH:54])=[CH:52][CH:53]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCS(C)(=O)=O)NC(=O)OC(C)(C)C
Product: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCS(C)(=O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C

Procedure:
Using BOC-(D)-Met(O2)-Gly-Phe-NHNH-COCH3 (0.52 g) and BOC-Tyr-ONB(0.46 g), the desired compound is obtained in a similar manner to (V) of Example 26. m.p. 176°-177° C. [α]D23 -2.9°(c=0.24, DMF), Rf1 =0.23.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16].CC1(C)C(C)(C)OB([C:27]2[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH:32]=2)O1>>[C:14]([NH:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:7][C:2]=1[C:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH:28]=1)(=[O:18])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C(=O)Nc1ccc(OC(F)(F)F)cc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: CC(C)C(=O)Nc1ccc(OC(F)(F)F)cc1C1=CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Prepared by Procedure W and Scheme AF using N-[2-bromo-4-(trifluoromethoxy)phenyl]-2-methylpropanamide and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate: ESMS m/e: 329.0 (M−100)+.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[C:7]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8]1>C1COCC1>[C:2]([O:4][C:7](=[O:14])[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])([CH3:5])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCCC(=O)O1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
Potassium tert-butoxide (2.7 g, 24 mmol) was dissolved in 17 mL of anhydrous THF at rt. After 5 min glutaric anhydride (2.4 g, 21 mmol) was added and the resulting suspension stirred for 2 h at rt. The reaction mixture was then quenched with 20 mL of 1 M KHSO4, extracted with 50 mL of EtOAc, adjusted to pH 2–3 with 1 M KHSO4 and extracted twice with 50 mL EtOAc. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give a yellow oil which was purified by silica gel flash chromatography (eluent: EtOAc:Hexanes- 1:1) to give 1.65 g (35% yield) pure (TLC) 1-2.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:33])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[CH:19]=3)[N:14]=2)=[CH:8][C:7]=1[CH2:31][CH3:32].[C:34](O)(=[O:37])[CH2:35][OH:36].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[CH:26]1([C:20]2[CH:19]=[C:18]([C:15]3[N:14]=[C:13]([C:9]4[CH:10]=[C:11]([CH3:12])[C:6]([O:5][CH2:4][C@@H:3]([OH:33])[CH2:2][NH:1][C:35](=[O:36])[CH2:34][OH:37])=[C:7]([CH2:31][CH3:32])[CH:8]=4)[O:17][N:16]=3)[CH:23]=[C:22]([O:24][CH3:25])[N:21]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1OC[C@@H](O)CN
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
To a solution of (2S)-1-amino-3-{4-[3-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-2-ethyl-6-methyl-phenoxy}-propan-2-ol (100 mg, 220 μmol), glycolic acid (22 mg, 289 μmol) and DIPEA (86 mg, 666 μmol) in DMF (3 mL), TBTU (93 mg, 289 μmol) is added. The mixture is stirred at rt for 1 h before it is diluted with EA (50 mL) and washed with sat. aq. NaHCO3 solution (20 mL) followed by brine (20 mL). The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (65 mg) as an almost colourless oil; LC-MS**: tR=0.84 min, [M+H]+=511.03; 1H NMR (CDCL3): δ1.33 (t, J=7.5 Hz, 3H), 1.68-1.79 (m, 2H), 1.82-1.95 (m, 4H), 2.05-2.15 (m, 2H), 2.41 (s, 3H), 2.76 (q, J=7.5 Hz, 2H), 3.18-3.28 (m, 1H), 3.49-3.59 (m, 1H), 3.75-3.95 (m, 3H), 4.01 (s, 3H), 4.18-4.26 (m, 3H), 7.08 (t, J=4.3 Hz, 1H), 7.49 (s, 1H), 7.91 (s, 1H), 7.93 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.[Cl:24]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1
Reactant: N#Cc1c(OCCc2ccccn2)nc(N)nc1-c1ccco1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: N#Cc1c(OCCc2ccccn2)nc(N)nc1-c1ccc(Cl)o1

Procedure:
From 2-amino-4-furan-2-yl-6-(2-pyridin-2-yl-ethoxy)-pyrimidine-5-carbonitrile and N-chlorosuccinimide in DMF. ES-MS m/e (%): 344 (M{37C }+H+, 30), 342 (M{35Cl}+H+, 100).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:24])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[CH:13][C:12]=2[O:19][CH2:20][CH:21]([F:23])[F:22])[CH2:5][CH2:4]1.[Cl:27][C:28]1[C:41]([N:42]=[C:43]=S)=[C:40]([Cl:45])[CH:39]=[CH:38][C:29]=1[CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].CC(C)N=C=NC(C)C>>[F:1][C:2]([F:25])([F:26])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[C:12]([O:19][CH2:20][CH:21]([F:22])[F:23])=[CH:13][C:14]3[NH:18][C:43]([NH:42][C:41]4[C:40]([Cl:45])=[CH:39][CH:38]=[C:29]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:34])([CH3:35])[CH3:36])[C:28]=4[Cl:27])=[N:17][C:15]=3[CH:16]=2)=[O:24])[CH2:5][CH2:4]1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: Nc1cc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Agent: CC(C)N=C=NC(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(OCC(F)F)cc3[nH]2)c1Cl

Procedure:
The title compound is prepared from N-(trans-4-trifluoromethyl-cyclohex-1-yl)-2-(2,2-difluoro-ethoxy)-4,5-diamino-benzoic acid amide and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide with DIC in analogy to example 1 g.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:21][C@@H:20]2[C@:7]([CH3:24])([CH2:8][CH2:9][C@H:10]3[C@H:19]2[CH2:18][CH2:17][C:16]2[C@:11]3([CH3:23])[CH:12]=[CH:13][C:14](=[O:22])[CH:15]=2)[C@H:3]1[C:4](=[O:6])[CH3:5].[Cl-].[Ca+2].[Cl-].[O-2].[Ca+2].[I:30]I>CO.C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[I:30][CH2:5][C:4](=[O:6])[C@@H:3]1[C@:7]2([CH3:24])[C@H:20]([C@H:19]3[C@H:10]([CH2:9][CH2:8]2)[C@:11]2([CH3:23])[C:16](=[CH:15][C:14](=[O:22])[CH:13]=[CH:12]2)[CH2:17][CH2:18]3)[CH2:21][C@H:2]1[CH3:1]
Reactant: II
Reactant: CC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@@]21C
Agent: [Ca+2]
Agent: [Cl-]
Agent: [O-2]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]2(C)[C@H]1C(=O)CI
Reaction time: 0.25 h

Procedure:
16α-Methylpregna-1,4-diene-3,20-dione (2.26 g), carbon tetrachloride (15 ml), methanol (7.3 ml) and calcium chloride in methanol (10%, 0.24 ml) are combined and stirred for 15 min at 25°-25°. Calcium oxide (2.50 g) is added and the mixture stirred an additional 5 min. A mixture of iodine (3.45 g), calcium chloride (10%, 5.4 ml) and methanol (2.4 ml) is added dropwise over 1 hr to the steroid mixture. After an additional 30 min the mixture is diluted with methylene chloride (100 ml), filtered through celite and concentrated. The residue is partitioned between methylene chloride and water, the phases are separated, the organic phase is washed with sodium sulfite, dried over magnesium sulfate and then concentrated to give the title compound, NMR (CDCl3) 0.7, 0.9, 1.2, 5.25, 5.35, 6.0, 6.2 and 7.9 δ.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[Cu][C:21]#[N:22].CCOC(C)=O>CN(C=O)C>[CH3:19][N:16]1[CH2:17][CH2:18][N:13]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([C:5]3[S:6][C:2]([C:21]#[N:22])=[CH:3][CH:4]=3)[CH:12]=2)[CH2:14][CH2:15]1
Reactant: CN1CCN(c2ccnc(-c3ccc(Br)s3)c2)CC1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccnc(-c3ccc(C#N)s3)c2)CC1

Procedure:
A mixture of 1-[2-(5-bromo-thiophen-2-yl)-pyridin-4-yl]-4-methyl-piperazine (41 mg, 0.13 mmol) and copper(I) cyanide (55 mg, 0.62 mmol) was heated in DMF at 180° C. by microwave for 30 minutes. After cooling, EtOAc was added and the resulting mixture was passed through Celite®. The filtrate was washed with water and the organic layer was concentrated. The resulting residue was purified by preparative TLC to yield the title compound.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2Cl)=[N:13][C:12]([Cl:17])=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(=O)C.C(O)(=O)C.[CH3:26][N:27]([CH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32][CH2:31]1)[CH3:28]>>[Cl:17][C:12]1[N:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5])=[C:15]2[NH:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([CH2:29][N:27]([CH3:28])[CH3:26])[CH2:31][CH2:32]1
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Reactant: O=C(c1cnc2ccc(Cl)nc2c1Cl)C1CC1
Solvent: CC(=O)O
Product: CN(C)C[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Cl)nc23)CC1

Procedure:
Following general procedure I, cyclopropyl(4,6-dichloro-1,5-naphthyridin-3-yl)-methanone (267 mg, 1.0 mmol) was reacted with trans-4-[(dimethylamino)methyl]cyclohexanamine diacetic acid salt (270 mg, 1.0 mmol) to afford the desired product (150 mg, 39%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 10.85 (br s, 1H), 9.19 (s, 1H), 8.08 (d, J=8.7 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 4.97 (br s, 1H), 2.72-2.62 (m, 1H), 2.31-2.24 (m, 2H), 2.22 (s, 6H), 2.13 (d, J=7.2 Hz, 2H), 1.96-1.89 (m, 2H), 1.55-1.46 (m, 1H), 1.36 (qd, J=12.4, 3.3 Hz, 2H), 1.28-1.22 (m, 2H), 1.21-1.09 (m, 2H), 1.08-1.02 (m, 2H); ESI MS m/z 387 [M+H].+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.[CH2:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[Na+].O>C1(C)C=CC=CC=1.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH2:17]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[CH:5]3)[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(CN2CCN(c3ccc4c(cnn4C4CCCCO4)c3)CC2)cc1
Temperature: 75 °C
Yield: 54.7 %

Procedure:
To a solution of the 5-bromo-1-tetrahydro-2H-pyran-2-yl-1H-indazole (250 mg, 0.889 mmol) obtained in Reference Example 5 in toluene (12 ml) were added 1-benzylpiperazine (0.24 ml, 1.35 mmol) and sodium tert-butoxide (128 mg, 1.33 mmol) at room temperature. After deaeration, bis(tri-o-tolylphosphine)-palladium(II) dichloride (70 mg, 0.0891 mmol) was added thereto and the resulting mixture was stirred at 75° C. for three and a half hours. Then, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate=5/2) to obtain 5-(4-benzyl-1-piperazinyl)-1-tetrahydro-2H-pyran-2-yl-1H-indazole (183 mg, 55%).
Reaction SMILES: [C:1]1([N:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH:2]=1.[C:11]([O:19][CH3:20])(=[O:18])[C:12]#[C:13][C:14]([O:16][CH3:17])=[O:15]>>[N:6]1([C:1]2[CH2:5][CH2:4][CH2:3][CH:2]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:12]=2[C:11]([O:19][CH3:20])=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C#CC(=O)OC
Reactant: C1=C(N2CCCC2)CCC1
Product: COC(=O)C1=CCCCC(N2CCCC2)=C1C(=O)OC

Procedure:
1-(1-Cyclopenten-1-yl)pyrrolidine and 2-butynedioic acid, dimethyl ester are reacted according to the procedure set forth in J.O. C., Vol. 28, p. 1464 (1963) to yield 3-(1-pyrrolidinyl)-2,7-cycloheptadiene-1,2-dicarboxylic acid, dimethyl ester.
Reaction SMILES: C(N(CP(O)(O)=O)CC(O)=O)C.[Cl:13]C(OCC1C=CC=CC=1)=O.C(=O)([O-])[O-].[Na+].[Na+].[ClH:30].[C:31]([N:41]([CH2:48][P:49]([OH:52])([OH:51])=[O:50])[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>O>[C:31]([N:41]([CH2:48][P:49]([O:51][Cl:13])([O:52][Cl:30])=[O:50])[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32]
Reactant: CCOC(=O)CN(CP(=O)(O)O)C(=O)OCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cl
Agent: CCN(CC(=O)O)CP(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)OCc1ccccc1

Procedure:
Ethyl N-phosphonomethylglycine (9.85 g., 0.05 mole) and benzyl chloroformate (9.4 g., 0.05 mole) were dissolved in 50 ml. of water and sodium carbonate (7.95 g., 0.075 mole) was added over a 1/2 hour period. The solution was stirred until all of the benzyl chloroformate had reacted. Concentrated hydrochloric acid (12.5 ml) was then added. Upon standing ethyl N-carbobenzoxy-N-phosphonomethylglycinate separated as an oil. The oil was then dried in a vacuum dessicator over phosphorus pentoxide at 0.55 torr. A 4 g. sample of the oil was dissolved in oxalyl chloride (20 ml) and stirred until gas evolution ceased. The mixture was concentrated in vacuo to yield ethyl N-carbobenzoxy-N-(dichlorophosphonomethyl)glycinate as a colorless oil. The oil is treated with an excess of oxalyl chloride to convert it to ethyl N-carbobenzoxy-N-phosphonomethylglycine dichloride which is then reacted with the appropriate thiol of the formula
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:19]([O-])=O.[F:22][CH:23]([F:33])[O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O.O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CN(C)C=O>[F:22][CH:23]([F:33])[O:24][C:25]1[CH:26]=[C:27]([C:28]2[NH:1][C:2]3=[N:7][C:6]([N:8]4[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:9]4)=[CH:5][CH:4]=[C:3]3[N:19]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: O=Cc1cccc(OC(F)F)c1
Reactant: CN(C)C(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)[C@@H]1CCCN(c2ccc3nc(-c4cccc(OC(F)F)c4)[nH]c3n2)C1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
Into a 4 mL vial was added (R)-1-(6-amino-5-nitropyridin-2-yl)-N,N-dimethylpiperidine-3-carboxamide (500 μL, 0.3M) dissolved in N,N-dimethylformamide followed by 3-(difluoromethoxy)benzaldehyde (950 μL, 0.158M) dissolved in N,N-dimethylformamide. Water (50 μL) was added followed by sodium hydrosulfite (574 μmol) under a nitrogen atmosphere. The vial was capped and shaken at 110° C. for 18 h. The solvent was removed by Speedvac and the residue was purified by HPLC to afford the title compound. MS (API-ES+) (M+H) 416.2; HPLC retention time 1.392 min (Method E).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9]\[CH2:10][OH:11])=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:49][O:50][C:51](=[O:62])[CH2:52][O:53][C:54]1[CH:59]=[CH:58][C:57](O)=[CH:56][C:55]=1[CH3:61]>O1CCCC1>[CH3:49][O:50][C:51](=[O:62])[CH2:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([O:11][CH2:10]/[CH:9]=[C:8](\[C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:56][C:55]=1[CH3:61]
Reactant: OC/C=C(/c1ccccc1)c1ccc(I)cc1
Reactant: COC(=O)COc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccccc2)c2ccc(I)cc2)cc1C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of (Z)-3-(4-Iodo-phenyl)-3-phenyl-prop-2-en-1-ol (756 mg, 2.249 mmol) in dry tetrahydrofuran (40 mL) was added tributylphosphine (0.61 ml, 3.37 mmol). The mixture was cooled to 0° C. and added 1,1′-(azodicarbonyl)dipiperidine (850 mg, 3.37 mmol) and after 10 min (4-Hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (485 mg, 2.47 mmol) was added. After 1.5 hr at 0° C. the reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was added silica gel Fluka 60 (10 g) and evaporated in vacuo. The residue was purified by ISCO combiflash 16 (silica gel, DCM/MeOH 90:10) giving (Z)-{4-[3-(4-iodo-phenyl)-3-phenyl-allyloxy]-2-methyl-phenoxy}-acetic acid methyl ester as an oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([N:23]5[CH2:26][CH2:25][C@@H:24]5[CH:27]5[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:33])=[N:5]1)([CH3:3])[CH3:2].[H][H].[CH3:36][C:37]([CH3:39])=O>[Pd]>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([N:23]5[CH2:26][CH2:25][CH:24]5[C@@H:27]5[CH2:32][CH2:31][CH2:30][N:29]([CH:37]([CH3:39])[CH3:36])[CH2:28]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:33])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)=O
Reactant: [H][H]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(N4CC[C@@H]4C4CCCNC4)cc2OCC3)n(C(C)C)n1
Agent: [Pd]
Product: Cc1nc(-c2cn3c(n2)-c2ccc(N4CCC4[C@@H]4CCCN(C(C)C)C4)cc2OCC3)n(C(C)C)n1
Yield: 40 %

Procedure:
To a solution of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-((R)-2-piperidin-3-ylazetidin-1-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (64.3 mg, 0.1436 mmol) in a mixture of IMS (5 mL) and acetone (1 mL) was added Pd/C (10%, 15 mg). The mixture was stirred at RT under a balloon of hydrogen for 16 h, then filtered through a celite pad. The filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-15% 2M NH3/MeOH in DCM), then C18, gradient 20-60% MeOH in 0.5% TFA/H2O) and then loaded in MeOH onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3/MeOH, affording 342 as a colourless foam (28 mg, 40%). LCMS (method K): RT 2.97 min [M+H]+ 490.2. 1H NMR (CD3OD, 400 MHz): δ 8.21 (1H, dd, J=8.7, 2.0 Hz), 7.61 (1H, s), 6.36-6.32 (1H, m), 6.13 (1H, dd, J=5.5, 2.3 Hz), 5.85 (1H, septet, J=6.6 Hz), 4.43 (4H, s), 4.10-3.91 (2H, m), 3.64 (1H, quintet, J=7.9 Hz), 3.06-2.87 (2H, m), 2.75 (1H, septet, J=6.4 Hz), 2.35 (3H, s), 2.33-2.08 (5H, m), 1.85-1.56 (3H, m), 1.51 (6H, d, J=6.6 Hz), 1.98 (0.5H, d, J=10.8 Hz), 1.25-1.11 (1H, m), 1.09 & 1.07 (6H, 2d, J=6.6 Hz)
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37]([CH2:39][C@@H:40]([OH:42])[CH3:41])[CH:38]=2)O1>>[F:21][C:20]([F:23])([F:22])[CH2:19][N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:34]5[CH:35]=[N:36][N:37]([CH2:39][C@@H:40]([OH:42])[CH3:41])[CH:38]=5)[CH:25]=[CH:24][C:5]=4[C:6]=3[N:7]=2)=[N:18][CH:17]=[N:16]1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: C[C@H](O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: C[C@H](O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with (S)-1-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 381. MS (ESI+) 477.1
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]O)=[CH:7][CH:6]=1.S(Br)([Br:15])=O>O1CCOCC1.CCOCC>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][Br:15])=[CH:7][CH:6]=1
Reactant: O=S(Br)Br
Reactant: OCc1ccc(OCCCl)cc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: ClCCOc1ccc(CBr)cc1
Reaction time: 0.08 h
Yield: 58 %

Procedure:
To 4-(2-Chloroethoxy)benzylalcohol CAS No. [111728-87-1] (6.4 g, 34.31 mmol) in dioxane (100 mL) at 0° C. was added slowly thionylbromide (7.13 g, 34.31 mmol). The reaction was run at 0° C. after 5 min. The reaction mixture was diluted with ether (200 mL) and washed with H2O (1×30 mL) then NaHCO3 (2×25 mL), and brine (30 mL). The organic extract was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (15% EtOAc/Hex) to yield 5.0 g (58%) of the desired product. Mp=64–66° C.; 1H NMR (DMSO) 7.37 (d, 2 H, J=8.8 Hz), 6.93 (d, 2 H, J=8.8 Hz), 4.68 (s, 2 H), 4.24 (t, 2 H, J=5.05 Hz), 3.93 (t, 2 H, J=5.27 Hz); MS eI m/z 248 (M+).