Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C@H:27]2[CH2:32][C@H:31]([N:33]3[CH2:38][CH2:37][N:36]([CH2:39][C:40]([NH:42][C:43]4[C:48]([CH3:49])=[CH:47][CH:46]=[CH:45][C:44]=4[CH3:50])=[O:41])[CH2:35][CH2:34]3)[CH2:30][CH2:29][NH:28]2)[CH:22]=[CH:23][C:24]=1[Cl:25].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:28]1[CH2:29][CH2:30][C@@H:31]([N:33]2[CH2:34][CH2:35][N:36]([CH2:39][C:40]([NH:42][C:43]3[C:48]([CH3:49])=[CH:47][CH:46]=[CH:45][C:44]=3[CH3:50])=[O:41])[CH2:37][CH2:38]2)[CH2:32][C@@H:27]1[CH2:26][C:21]1[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=1)=[O:7]
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN([C@@H]2CCN[C@@H](Cc3ccc(Cl)c(Cl)c3)C2)CC1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=O)CN1CCN([C@@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](Cc3ccc(Cl)c(Cl)c3)C2)CC1
Reaction time: 0.08 h
Yield: 43.9 %

Procedure:
3,5 di(trifluormethyl)benzoyl chloride (0.0011 mol) was added to a mixture of (±)-trans-4-[2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (0.001 mol) in DCM (20ml). The mixture was stirred for 5 minutes. Triethylamine (2ml) was added. The mixture was stirred at RT for 3 hours, washed with a diluted NaOH solution and with water, and then dried. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 96/4). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.32 g (44%) of (±)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (compound 139).
Reaction SMILES: [O:1]1[C:9]2[C:8]([OH:10])=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[N+:11]([O-])([OH:13])=[O:12]>>[N+:11]([C:7]1[N:6]=[CH:5][C:4]2[CH:3]=[CH:2][O:1][C:9]=2[C:8]=1[OH:10])([O-:13])=[O:12]
Reactant: Oc1cncc2ccoc12
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1ncc2ccoc2c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
The reaction was conducted with 1 g starting material/10 mL 90% aq. nitric acid ratio. Reactions were run at 2×200 mg, 500 mg, 4×1.05 g scales. The nitric acid was cooled down to 0° C. and furo[3,2-c]pyridin-7-ol was added in portions slowly. The color of the reaction mixture turned to deep orange/red. The reaction mixture was stirred at 0° C. for 30 min. LC-MS showed complete consumption of the starting material. The mixture was poured into crashed ice to quench reaction, then extracted with DCM (3×10 mL for 200 mg scale). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The resulting yellow solid (1.83 g, 26% yield) was directly used in the next step. 1H NMR (CD3OD, 400 MHz): δ=7.16 (d, J=2.0 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 8.39 (s, 1H). MS (ES+): 181.01 [MH+].
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:35]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][C@@H:43]1[CH3:48])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C(N(CC)CC)C>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:45]4[CH2:46][CH2:47][N:42]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@@H:43]([CH3:48])[CH2:44]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (80.0 mg, 0.155 mmol) and (S)-1-boc-2-methylpiperazine (93.1 mg, 0.465 mmol) in 1,4-dioxane (2 mL) was added triethylamine (156.8 mg, 0.19 mL, 1.549 mmol). The reaction mixture was stirred at 40° C. for 4 h, at room temperature overnight, then at 40° C. for an additional 7 h. The reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C35H43ClN5O5S (M+H+): 680.3; Found: 680.0 (M+H+).
Reaction SMILES: Cl[CH2:2][Si:3]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[Na].[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>CN(C)C=O.O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([Si:3]([CH3:5])([CH3:4])[CH2:2][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:7][CH:8]=1
Reactant: C[Si](C)(CCl)c1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(Cn1ccnc1)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A mixture of 2.2 g (0.010 mol) of chloromethyl(4-chlorophenyl)dimethylsilane and 1.1 g (0.012 mol) of imidazole sodium salt in 5 ml of dimethylformamide was stirred at 80°-90° for 2 hours, cooled, diluted with water, and extracted with ether. The ether solution was washed with water and brine, dried over magnesium sulfate, and evaporated to leave 2.0 g (81%) of the title compound as a yellow liquid: nD20 1.5472; ir (neat) 1560, 1495, 1480, 1375, 1250, 1105, 1080, 905, 830, 810, 740 cm-1 ; nmr (CDCl3) 0.3 (6H, s), 3.6 (2H, s), 6.6 (1H, broad s), 6.9 (1H, broad s), 7.1 (1H, broad s), 7.3 (4H, s).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[CH:26]=[C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=5)[S:28][C:21]=34)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[CH:26]=[C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH2:33][NH:9][CH2:8][CH2:7][N:1]6[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]6)=[CH:31][CH:30]=5)[S:28][C:21]=34)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: NCCN1CCNCC1
Reactant: O=Cc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Product: c1cc(Nc2ccc3[nH]ccc3c2)c2sc(-c3ccc(CNCCN4CCNCC4)cc3)cc2n1

Procedure:
The title compound was prepared from 2-piperazin-1-yl-ethylamine and 4-[7-(1H-indol-5-ylamino)-thieno(3,2-b]pyridin-2-yl]-benzaldehyde by a procedure analogous to example 17. LC-MS: 483 (MH+); HPLC RT: 3.41 minutes.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][CH2:5]Br.[C:7]([O-:10])(=[O:9])[CH3:8].[Na+]>C(O)C>[C:7]([O:10][CH2:2][CH:3]=[CH:4][CH2:5][O:10][C:7](=[O:9])[CH3:8])(=[O:9])[CH3:8]
Reactant: BrCC=CCBr
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)OCC=CCOC(C)=O
Reaction time: 1 h

Procedure:
After adding 1 g of 1,4-dibromo-2-butene (available from Sigma-Aldrich Co.) and 3 g of sodium acetate (available from Wako Pure Chemical Industries, Ltd.) into ethanol, reflux was conducted at 80° C. for 1 hour, to obtain 1,4-diacetoxy-2-butene. 1,4-diacetoxy-2-butene was dissolved in 30 ml of ethanol, and 20 ml of an aqueous sodium hydroxide solution (1 mol/l) was added, to synthesize 2-butene-1,4-diol.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]([C:13]1[CH:14]=[C:15]([P:25](=[O:52])([C:36]2[CH:41]=[C:40]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:39]([O:46][CH3:47])=[C:38]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:37]=2)[C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:16]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]=1[O:19][CH3:20])([CH3:12])([CH3:11])[CH3:10].CCCCCC>C(Cl)Cl>[Br:8][C:27]1[C:28]([O:34][CH3:35])=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:26]=1[P:25](=[O:52])([C:36]1[CH:37]=[C:38]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:39]([O:46][CH3:47])=[C:40]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:41]=1)[C:15]1[CH:16]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([O:19][CH3:20])=[C:13]([C:9]([CH3:10])([CH3:11])[CH3:12])[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(OC)cc(P(=O)(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c1
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1cc(OC)c(Br)c(P(=O)(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
NBS (206 g, 115.7 mmol) was added to a solution of bis(3,5-di-tert-butyl-4-methoxyphenyl)(3,5-dimethoxyphenyl)phosphine oxide (70 g, 112.4 mmol) in CH2Cl2 (350 mL) at 0° C. The resulting suspension was stirred at 0° C. for 1 h then was warmed to RT and stirred for 4 h. The reaction was monitored by TLC until no starting material remained. The solution was washed with conc. Na2CO3 (300 mL×2) at RT. The organic layer was separated and dried over MgSO4. It was filtered and the solvent was removed to give the crude product. Hexane (400 mL) was added and the solution concentrated to 300 mL. It became cloudy and a white solid precipitated. Another 100 mL of hexane was added. The suspension was stirred at RT for 2 h. It was filtered and the solid dried under vacuum to give the product as a colourless solid (64.4 g). A second crop (7.2 g) was obtained from the mother liquor. Overall yield=90.9%. 1H NMR (400 MHz, CDCl3) δ: 7.55 (d, J=13.2 Hz, 4H), 7.04 (dd, J1=13.2 Hz, J2=2.8 Hz, 1H), 6.65 (d, J=2.8 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.68 (s, 6H), 1.36 (s, 36H). 31P NMR (162.0 MHz, CDCl3) δ: 32.4.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[CH:32][N:31]=2)[CH2:26][CH2:25]1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:34]3[CH:33]=[CH:32][N:31]=[C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)[CH:35]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3[nH]nc(I)c3cn2)c1F
Reactant: CN1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccnc(N5CCN(C)CC5)c4)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine. LCMS (M+H)+=467.2.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[CH2:7]([CH:9]1[CH2:13][C:12](=O)[CH2:11][CH:10]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:7]([CH:9]1[CH2:13][C:12](=[CH2:1])[CH2:11][CH:10]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)C1CC(=O)CC1CC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CC(CC)C(C(=O)OCC)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
A solution of KOt-Bu (3.65 g, 32.6 mmol) and methyltriphenylphosphonium bromide (11.6 g, 32.6 mmol) in THF (69.5 mL) was cooled to about −10° C. A solution of ethyl 2-ethyl-4-oxocyclopentanecarboxylate (4.00 g, 21.7 mmol) in THF (17.4 mL) was added dropwise while the temperature was kept at about 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for about 16 h. The insoluble material was removed by filtration. The filtrate was concd under reduced pressure. The resulting material was purified by silica gel (120 g) chromatography eluting with a gradient of 0-20% EtOAc in heptane to provide ethyl 2-ethyl-4-methylenecyclopentanecarboxylate (2.55 g, 64%) as a colorless liquid: 1H NMR (d-DMSO) δ 4.88-4.78 (m, 2H), 4.16-3.96 (m, 2H), 2.66-2.31 (m, 4H), 2.24-1.82 (m, 2H), 1.50 (m, 1H), 1.35-1.22 (m, 1H), 1.18 (t, 3H), 0.85 (m, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][NH:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH2:20][O:21][CH3:22])[C:15]2=[O:23])=[CH:9][N:8]=1)[CH3:3].[Cl:24][C:25]1[S:29][C:28]([O:30][CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[Cl:24][C:25]1[S:29][C:28]([O:30][CH2:31][C:32]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][C:10]3[CH:9]=[N:8][C:7]([NH:6][CH2:5][CH2:4][N:2]([CH3:1])[CH3:3])=[N:12][CH:11]=3)[C:15](=[O:23])[C@@H:16]2[CH2:20][O:21][CH3:22])=[O:33])=[CH:27][CH:26]=1
Reactant: COC[C@@H]1NCCN(Cc2cnc(NCCN(C)C)nc2)C1=O
Reactant: O=C(O)COc1ccc(Cl)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC[C@H]1C(=O)N(Cc2cnc(NCCN(C)C)nc2)CCN1C(=O)COc1ccc(Cl)s1
Reaction time: 12 h

Procedure:
The title compound can be prepared by placing 1-[(2-{[N,N-dimethylaminoethyl]-amino}-pyrimidin-5-yl)-methyl]-3-(S)-methoxymethyl-piperazine-2-one, (5-chloro-thiophen-2-yloxy)-acetic acid, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate and triethylamine in DMF and stirring 8-16 h. The mixture is evaporated and is diluted with ethyl acetate. The organic phase is washed with water, 2 N HCl, 1 N NaOH and brine, is dried (MgSO4) and is evaporated. The residue is purified by flash chromatography (silica gel, 4:1 ethyl acetate/hexanes) to provide the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(=O)=O.[Li]CCCC.[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1.CCOCC>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: c1ccc2occc2c1
Reactant: CCOC(=O)C(=O)OCC
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
To a solution of benzofuran (0.250 mL, 2.32 mmol) in tetrahydrofuran (12.5 mL) stiffing at −100° C. (CO2, ether bath) was added n-BuLi (1.377 mL, 2.203 mmol, 1.6 M in hexanes). The reaction was stirred for 30 min (yellow color) and added dropwise via a canulated into a solution of diethyl oxalate (0.314 mL, 2.32 mmol) in tetrahydrofuran (7 mL) stiffing at −100° C. The reaction mixture was stirred for 1 h and then quenched with saturated aqueous ammonium chloride solution. The mixture was warmed to rt, diluted with dichloromethane, and washed with 0.1 N HCl. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluted with dichloromethane). The fractions containing the title compound were collected and repurified by flash chromatography on silica gel (25% acetone/hexane) to provide the title compound (ethyl 2-(benzofuran-2-yl)-2-oxoacetate, 237 mg, 47% yield).
Reaction SMILES: C(N(CC)CC)C.[OH:8]/[N:9]=[C:10](\[NH2:20])/[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[C:14]([CH3:19])[CH:13]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>ClCCl>[OH:8]/[N:9]=[C:10](\[NH:20][C:22](=[O:23])[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)/[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[C:14]([CH3:19])[CH:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc(C/C(N)=N/O)ccc1I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C/C(=N/O)NC(=O)Oc2ccccc2)ccc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.7 %

Procedure:
Triethylamine (0.651 mL, 4.67 mmol) was added to (Z)—N′-hydroxy-2-(4-iodo-3-methylphenyl)acetimidamide (Intermediate 29-3; 1.13 g, 3.90 mmol) in dry dichloromethane (30 mL) at 0° C. The resulting yellow solution was stirred at 0° C. for 1 hour. Phenyl chloroformate (0.598 mL, 4.67 mmol) was added and the reaction mixture stirred at 0° C. for a further 1 hour. The solution was washed sequentially with saturated Na2CO3 (50 mL) and water (50 mL×2). The organic layer was dried over MgSO4, filtered and evaporated to afford (Z)-phenyl 1-(hydroxyimino)-2-(4-iodo-3-methylphenyl)ethylcarbamate (1.675 g, 105%) as crude product.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:16](=O)[NH2:17])=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>O1CCCC1>[Br:1][C:2]1[C:3]([C:16](=[S:28])[NH2:17])=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(N)=O)c(Br)cn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(C(N)=S)c(Br)cn1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
The crude tert-butyl 5-bromo-4-carbamoylpyridin-2-ylcarbamate (Intermediate 84, 232 mmol) was treated with Lawesson's Reagent (94 g, 232 mmol, 1 eq) and tetrahydrofuran (700 mL), the resulting mixture was heated at reflux for 1 h, then it was allowed to stir at room temperature over the weekend. The mixture was concentrated to dryness in vacuo and toluene (˜300 mL) was added. A bright yellow solid precipitated formed which was collected by filtration and washed with toluene, then dried in the vacuum oven at 50° C. for 4 h, yielding 75 g of a bright yellow solid (97%).
Reaction SMILES: Cl.NO.C([N:6]([CH2:9][CH3:10])CC)C.[Br:11][C:12]1[CH:13]=C(C=O)[S:15][C:16]=1[Cl:17].C1(=O)OC(=O)C2=CC=CC=C12>C(#N)C.C(OCC)(=O)C>[Br:11][C:12]1[CH:13]=[C:10]([C:9]#[N:6])[S:15][C:16]=1[Cl:17]
Reactant: O=Cc1cc(Br)c(Cl)s1
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Agent: O=C1OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1cc(Br)c(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Hydroxylamine hydrochloride (Aldrich, 4.91 g, 70.66 mmol) and triethylamine (anhydrous, 11.2 mL, 80.36 mmol) were added to a 0° C. solution of 4-bromo-5-chloro-thiophene-2-carbaldehyde (Example 24: step a, 10.63 g, 47.14 mmol) in acetonitrile (anhydrous, 250 mL). The reaction mixture was warmed to room temperature and stirred for 1 hour. Phthalic anhydride was added and the reaction mixture was heated to 80° C. overnight. The mixture was cooled to room temperature, diluted with ethyl acetate (400 mL), and washed with aqueous citric acid, saturated NaHCO3, water, and brine. The organic layer was dried over magnesium sulfate, filtered, concentrated in vacuo, and purified by column chromatography (silica gel, 5% ethyl acetate/hexanes) to afford the title compound as a pale yellow solid (9.76 g, 93% yield). 1H-NMR (CDCl3): δ 7.47 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[O:7][CH2:6][C:5]([CH2:20][CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[C:23]2[N+:27]([O-:29])=[O:28])([CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][O:3]1.C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.[F-:57].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:1][C:2]1([CH3:30])[O:7][CH2:6][C:5]([CH2:8][F:57])([CH2:20][CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[C:23]2[N+:27]([O-:29])=[O:28])[CH2:4][O:3]1
Reactant: Cc1ccc(S(=O)(=O)OCC2(CCn3ccnc3[N+](=O)[O-])COC(C)(C)OC2)cc1
Reactant: [F-]
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1(C)OCC(CF)(CCn2ccnc2[N+](=O)[O-])CO1

Procedure:
5 mg (11.4 μmol equivalents) of 2,2-dimethyl-5-[2-(2-nitro-1H-imidazol-1-yl)ethyl]-5-(p-toluenesulfonyloxymethyl)-1,3-dioxane was dissolved in 1 mL of acetonitrile, 14 mg (34.5 μmol equivalents) of Kryptofix 222 (trade name, Merck), 0.82 g (14.1 μmol equivalents) of potassium fluoride, and 0.4 mg (2.9 μmol equivalents) of potassium carbonate were added thereto, and the mixture was refluxed while heating for 5 hours. After completion of the reaction, water was added and the mixture was extracted three times with chloroform. The combined chloroform layers were dried with anhydrous magnesium sulfate and subsequently concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography to give a trace amount of 2,2-dimethyl-5-fluoromethyl-5-[2-(2-nitro-1H-imidazol-1-yl)ethyl]-1,3-dioxane.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:13]([N:14]2[N+:18]([O-:19])=[C:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C:16]3=[N:15]2)=[CH:12][C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1.[CH2:24](Br)[C:25]#[CH:26].O>CN(C)C=O>[CH2:26]([N:8]1[C:7]2[CH:12]=[C:13]([N:14]3[N+:18]([O-:19])=[C:17]4[CH2:20][CH2:21][CH2:22][CH2:23][C:16]4=[N:15]3)[C:4]([F:3])=[CH:5][C:6]=2[S:10][C:9]1=[O:11])[C:25]#[CH:24]
Reactant: C#CCBr
Reactant: O=c1[nH]c2cc(-n3nc4c([n+]3[O-])CCCC4)c(F)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCn1c(=O)sc2cc(F)c(-n3nc4c([n+]3[O-])CCCC4)cc21

Procedure:
To a dispersion of sodium hydride (60% oil; 31 mg) in dry N,N-dimethylformamide (3 ml) was added 2-[6-fluoro-2(3H)-benzothiazolon-5-yl]-4,5,6,7-tetrahydro-2H-benzotriazole-1-oxide (220 mg) at 0° C., and the resultant mixture was stirred at the same temperature for 30 minutes, followed by addition of propargyl bromide (94 mg). The mixture was allowed to react at 50° to 60° C. for 3 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel thin layer chromatography using a mixture of ethyl acetate and toluene (1:9) as an eluent to give 2-[3-(2-propynyl)-6-fluoro-2(3H)-benzothiazolon-5-yl]-4,5,6,7-tetrahydro-2H-benzotriazole-1-oxide (Compound No. 5; 120 mg). nD25.4 1.5988.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][C:16]#[N:17])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2.N.CO>CO.O1CCCC1.[Co]>[Cl:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][CH2:16][NH2:17])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2
Reactant: Cn1cc2c3c(c(Cl)cc2n1)CCC3=CC#N
Agent: [Co]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc2c3c(c(Cl)cc2n1)CCC3=CCN
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.6 %

Procedure:
(5-Chloro-2-methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-ylidene)acetonitrile (116 mg, 2.87 mmol) was dissolved in a mixture of methanol (5 mL) and tetrahydrofuran (5 mL), Raney cobalt (1 g) and 8M ammonia/methanol solution (2 mL) were added to the solution, and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hr. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to give the title compound (118 mg, yield 100%).