Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[N:6]([C@@H:8]([C:12]2[O:13][C:14]3[C:19]([C:20](=[O:29])[C:21]=2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=[C:16]([Cl:30])[CH:15]=3)[CH:9]([CH3:11])[CH3:10])[CH:7]=1.N1C=CC=CC=1.[CH3:44][C:45](OC(C)=O)=[O:46]>>[CH2:22]([CH:21]1[C:20](=[O:29])[C:19]2[C:14](=[CH:15][C:16]([Cl:30])=[CH:17][CH:18]=2)[O:13][CH:12]1[C@H:8]([N:6]1[CH:7]=[C:3]([CH2:2][NH:1][C:45](=[O:46])[CH3:44])[N:4]=[C:5]1[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)[CH:9]([CH3:11])[CH3:10])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(-c2nc(CN)cn2[C@@H](c2oc3cc(Cl)ccc3c(=O)c2Cc2ccccc2)C(C)C)cc1
Solvent: c1ccncc1
Product: CC(=O)NCc1cn([C@H](C(C)C)C2Oc3cc(Cl)ccc3C(=O)C2Cc2ccccc2)c(-c2ccc(C)cc2)n1
Yield: 88.8 %

Procedure:
To 2-[(R)-1-(4-aminomethyl-2-p-tolyl-imidazol-1-yl)-2-methyl-propyl]-3-benzyl-7-chloro-chromen-4-one (0.17 g, 0.33 mMol) in CH2Cl (5 mL) was added with stirring, pyridine (27 uL, 0.33 mMol) and Ac2O (63 uL, 0.67 mMol). After stirring at RT for 4 h the reaction was concentrated under vacuum. The remaining residue was triturated with (1:1) Et2O/pet. ether, filtered and dried under vacuum to give the title compound (163 mg, 89%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=8.6 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.43 (m, 6H), 7.17 (m, 3H), 6.84 (br s, 1H), 6.71 (d, J=2.2 Hz, 1H), 6.69 (s, 1H), 5.07 (d, J=10.9 Hz, 1H), 4.50 (2d, 1H), 4.43 (2d, 1H), 4.07 (d, J=15.5 Hz 1H), 2.66 (m, 1H), 2.51 (s, 3H), 2.48 (d, J=15.5 Hz, 1H), 2.00 (s, 3H), 0.95 (d, 6.6 Hz, 3H), 0.34 (d, J=6.7 Hz, 3H); MS (ES) m/e 554.4 (M+14)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@H:5]1[O:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:6]1.C(=O)([O-])O.[Na+].[Cl:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)(Cl)Cl>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[CH2:11][N:7]1[CH2:8][CH2:9][O:10][C@@H:5]([CH2:4][NH:3][C:27](=[O:28])[CH2:26][Cl:25])[CH2:6]1
Reactant: NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(CCl)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2S)-2-Aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (30.5 g) was added to chloroform (400 mL) and saturated aqueous sodium hydrogen carbonate solution (400 mL). After dropwise addition of chloroacetyl chloride (7.7 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hrs. After completion of the reaction, the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (31.6 g) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]3[N:20]=[CH:21][CH:22]=[C:23]([N:24]4[CH2:28][CH2:27][C@H:26]([N:29]([CH2:37][CH3:38])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]4)[C:6]=3[C:5]=2[CH:4]=1)#[N:2].[B-](F)(F)(F)[F:40].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:40][C:22]1[CH:21]=[N:20][C:7]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:19])[CH3:17])[C:9]3[CH:10]=[N:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[C:6]=2[C:23]=1[N:24]1[CH2:28][CH2:27][C@H:26]([N:29]([CH2:37][CH3:38])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:25]1
Reactant: F[B-](F)(F)F
Reactant: CCN(C(=O)OC(C)(C)C)[C@H]1CCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CCN(C(=O)OC(C)(C)C)[C@H]1CCN(c2c(F)cnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A mixture of (S)-tert-butyl 1-(6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yl)pyrrolidin-3-yl(ethyl)carbamate (290 mg, 0.54 mmol) and Selectfluor™ (957 mg, 2.7 mmol) in acetonitrile (4.5 mL) was stirred at 0° C. for 5 minutes. The cooled reaction mixture was quenched with saturated aqueous sodium thiosulfate, diluted with ethyl acetate (50 mL), and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a pale yellow foam, which was used in the next step without any further purification (120 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39](O)=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[N:5]=1)([CH3:3])[CH3:2].[CH:47]1([S:50]([NH2:53])(=[O:52])=[O:51])[CH2:49][CH2:48]1.ClC1C(OC)=CC=C2C=1N=C(C1SC=C(C(C)C)N=1)C=C2OC1CC2C(C(=O)N(C)CCCCC=CC3C(C(NS(C4CC4)(=O)=O)=O)(NC2=O)C3)C1>>[CH:1]([C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:53][S:50]([CH:47]6[CH2:49][CH2:48]6)(=[O:52])=[O:51])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3ccc(C(C)C)n3)nc2c1C
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3ccc(C(C)C)n3)nc2c1C

Procedure:
The title compound was prepared from 17-[2-(3-isopropylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (65) and cyclopropylsulfonamide following the procedure reported for the preparation of N-[17-[8-chloro-2-(4-isopropylthiazole-2-yl)-7-methoxy quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]-octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (56): m/z=733 (M+H)+. 1H NMR (CDCl3): 0.80-1.50 (m, 12H), 1.65-1.78 (m, 1H), 1.79-2.05 (m, 4H), 2.15-2.31 (m, 1H), 2.32-2.48 (m, 2H), 2.49-2.63 (m, 5H), 2.84-2.96 (m, 2H), 3.03 (s, 3H), 3.05-3.14 (m, 1H), 3.33-3.42 (m, 2H), 3.61-3.70 (m, 1H), 3.96 (s, 3H), 4.60 (t, J=12.3 Hz, 1H), 5.04 (t, J=10.6 Hz, 1H), 5.26-5.46 (m, 1H), 5.61-5.69 (m, 1H), 6.32 (d, J=2.5 Hz, 1H), 6.37 (br s, 1H), 7.13 (d, J=9.0 Hz, 1H), 7.30 (s, 1H), 7.95 (d, J=9.0 Hz, 1H), 8.68 (d, J=2.5 Hz, 1H), 10.88 (br s, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([CH2:19][NH:20][C:21]([NH:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:22])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:38]([O:46][C@H:47]1[C@@H:51]([O:52][C:53](=[O:60])[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C@@H:50](OC(=O)C)[O:49][C@@H:48]1[C:65]([NH:67][CH2:68][CH3:69])=[O:66])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(O[C@H]1[C@@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C)O[C@@H]1C(NCC)=O)(=O)C1C=CC=CC=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>ClC(Cl)(Cl)C.C(OCC)(=O)C>[C:38]([O:46][C@H:47]1[C@@H:51]([O:52][C:53](=[O:60])[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C@H:50]([N:14]2[CH:13]=[N:12][C:11]3[C:15]2=[N:16][C:17]([CH2:19][NH:20][C:21]([NH:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:22])=[N:18][C:10]=3[NH:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:49][C@@H:48]1[C:65]([NH:67][CH2:68][CH3:69])=[O:66])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(NCCN1CCCCC1)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: CCNC(=O)[C@H]1O[C@H](OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: CCNC(=O)[C@H]1O[C@@H](OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)NCCN4CCCCC4)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N,O-Bistrimethylsilylacetamide (0.34 ml, 1.4 mmol) was added to a stirred suspension of N-({6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-N′-[2-(1-piperidinyl)ethyl]urea (100 mg, 0.2 mmol) (Preparation 5) in 1,1,1-trichloroethane (20 ml) at 50° C. The reaction mixture was stirred at this temperature for 30 minutes, allowed to cool to room temperature and then evaporated under reduced pressure. Toluene (5 ml) was added and the solvent was removed under reduced pressure. The residue was redissolved in toluene (20 ml). (2S,3S,4R,5R)-5-(Acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate and (2S,3S,4R,5S)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (Preparation 18) and then trimethylsilyltrifluoromethanesulphonate (0.1 ml, 0.35 mmol) were added and the reaction mixture was heated under reflux for 2 hours. The reaction was then allowed to cool to room temperature and diluted with ethyl acetate (100 ml). The solution was washed with saturated aqueous sodium hydrogen carbonate solution (2×50 ml) and saturated aqueous sodium chloride solution (50 ml) and then dried (anhydrous magnesium sulphate). The solvent was removed to give a residue that was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 by volume). This gave an impure oil (100 mg) which was used without further purification in subsequent experiments.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH3:8])[CH:2]=1.[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].C1C=CC=CC=1.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:16]([O:15][C:13](=[O:14])[C:12]([C:10]#[N:11])=[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:8])[CH3:17]
Reactant: CC(=O)c1cccnc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=C(C)c1cccnc1

Procedure:
1-Pyridin-3-yl-ethanone, ethyl cyanoacetate, benzene, ammonium acetate, and acetic acid were refluxed for 16 hrs in a 250 mL round bottomed flask fitted with a Dean-Stark trap. The solutions were washed with water and brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography to yield the product as an oil. MS (ESI+) for C12H12N2O2 m/z 217.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:12][OH:13]>CC(N(C)C)=O.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:6]3[CH2:7][CH2:8][CH2:9][C@@H:10]([CH2:12][OH:13])[CH2:5]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: Fc1ccc2nnc(Cl)n2c1
Reactant: CO
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: OC[C@@H]1CCCN(c2nnc3ccc(F)cn23)C1
Yield: 29 %

Procedure:
A brown solution of Intermediate 24b (565 mg, 3.29 mmol) and R-3-hydroxymethyl piperidine (Chess GmbH, 948 mg, 8.23 mmol) in DMA (10 mL) was irradiated at 175° C. for 3 h in the microwave. The cooled solution was concentrated in vacuo, suspended in water (10 mL) and brine (10 mL), and then extracted with DCM (2×20 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to leave a brown oil. FCC, using 4-5% MeOH in DCM, gave the title compound as a viscous yellow oil (237 mg, 29%). LCMS (Method 3): Rt 2.11 min, m/z 251 [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:8]=[CH:9][C:10]=1Cl)[C:5](O)=[O:6].O1CCCC1.B(F)(F)F.O1CCCC1.O.C(Cl)[Cl:29]>>[NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:8]=[C:9]([Cl:29])[CH:10]=1)[CH2:5][OH:6]
Reactant: Nc1c(Cl)ccc(C(=O)O)c1Cl
Reactant: ClCCl
Agent: FB(F)F
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(Cl)cc(CO)c1Cl
Temperature: 8 °C
Reaction time: 1 h

Procedure:
Into a 1 liter three-neck flask was introduced 40 g (0.19 mole) of 3-amino-2,4-dichlorobenzoic acid and 150 ml of tetrahydrofuran. The solution was cooled to 8°-10° C. in an ice bath. A borontrifluoride-tetrahydrofuran (1M) solution (280 ml) was added dropwise over a period of 1 hr. After being stirred at 8° C. for an additional 1 hr. the solution was allowed to warm up slowly to room temperature. The reaction flask was then cooled again in an ice bath and 50 ml of water was added through a dropping funnel. The mixture was taken into 1 liter of methylene chloride and washed once with NaHCO3 and twice with water, then dried over calcium sulfate. The methylene chloride solution afforded 19.2 g of crude solid product, mp 111-121. Five grams of the crude solid was recrystallized from acetonitrile to yield 4.2 g of 3-amino-2,5-dichlorobenzyl alcohol; mp 121-127; nmr (DMSO-d6) δ4.50 (D, 2H), 5.34 (t, 1H), 5.52 (S, 2H), 6.73 (S, 2H); ir (CHCl3) 3490, 3380, 3240, 1630 and 1598 Cm-1.
Reaction SMILES: P(Br)(Br)Br.Br[CH2:6][C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])=[CH:10][CH:11]=1.[NH:21]1[CH:28]=[CH:27][C:25](=[O:26])[NH:24][C:22]1=[O:23].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C=O)C>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[O:8][C:7]([CH2:6][N:21]2[CH:28]=[CH:27][C:25](=[O:26])[NH:24][C:22]2=[O:23])=[CH:11][CH:10]=1)([O-:20])=[O:19]
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CBr)o1
Agent: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1ccn(Cc2ccc(-c3ccccc3[N+](=O)[O-])o2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.8 %

Procedure:
To a solution of alcohol in dichloromethane at 0° C. was added neat PBr3 in ice bath. The solution was allowed to warm to 25° C. and then stirred for 12 h. The reaction was quenched with ice and extracted with ethyl acetate. The combined organic layers were washed with H2O, sat. NaHCO3 and brine, and dried over anhydrous Na2SO4. After the solution was filtered and concentrated under reduced pressure, the crude compound was used for the subsequent alkylation without further purification. To a solution of 2-(bromomethyl)-5-(2-nitrophenyl)furan 11a (120 mg, 0.43 mmol) and uracil (476 mg, 4.3 mmol) in anhydrous DMF (2.0 mL) was added anhydrous potassium carbonate (235 mg, 1.7 mmol) at 25° C. The resulting solution was then heated at 50° C. for 8 h. After removal of DMF under reduced pressure, the residue was diluted with CHCl3 and washed three times with water. The organic layer was dried over anhydrous MgSO4 and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate to afford 90 mg (68%) of the uracil 13a as a white solid. 1H NMR (DMSO) δ: 11.29 (1H, s), 7.82 (1H, d, J=8.1 Hz), 7.77 (1H, d, J=7.5 Hz), 7.68 (1H, t, J=7.2 Hz), 7.60 (1H, d, J=7.8 Hz), 7.52 (1H, t, J=8.1 Hz), 6.83 (1H, d, J=3.6 Hz), 6.53 (1H, d, J=3.3 Hz), 5.57 (1H, dd, J=7.8, 1.5 Hz), 4.88 (2H, s); 13C NMR (DMSO) δ: 164.08, 151.69, 151.07, 148.39, 147.33, 145.33, 132.91, 129.70, 129.04, 124.36, 122.84, 110.38, 111.18, 102.01, 43.74.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].I[CH2:14][CH3:15].O>CCO>[CH2:14]([S:12][C:9]1[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1)[CH3:15]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCSc1ccc([N+](=O)[O-])cc1
Yield: 59.7 %

Procedure:
To a solution of NaOH (0.13 g, 3.2 mmol) in EtOH (10 mL) was added 4-nitrothiophenol (0.50 g, 3.2 mmol) and iodoethane (0.26 mL, 3.2 mmol). After stirring 2h the reaction mixture was added to water (30 mL) and extracted with Et2O (3×25 mL). The combined extracts were washed with satd NH4Cl (3×25 mL) and brine, dried (MgSO4) and concentrated under reduced pressure. The crude material was chromatographed (silica, EtOAc/Hex 0:100 to 30:70) to yield 1-ethylthio-4-nitrobenzene (0.35 g, 59%) as a yellow crystalline solid. 1H-NMR (CDCl3) δ 8.13 (2H, d, J=8.8), 7.32 (2H, d, J=8.8), 3.06 (2H, q, J=7.3), 1.41 (3H, t, J=7.3).
Reaction SMILES: [C:1]([P:5]([C:11]([F:20])([F:19])[C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)([C:7]([CH3:10])([CH3:9])[CH3:8])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH:26](OCC)=[O:27].[NH4+].[Cl-]>CCOCC>[C:1]([P:5]([C:11]([F:20])([F:19])[C:12]1[CH:17]=[CH:16][C:15]([CH:26]=[O:27])=[CH:14][CH:13]=1)([C:7]([CH3:10])([CH3:9])[CH3:8])=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC=O
Reactant: CC(C)(C)P(=O)(C(C)(C)C)C(F)(F)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)P(=O)(C(C)(C)C)C(F)(F)c1ccc(C=O)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To compound 27 (50 mg, 0.12 mmol ) in anhydrous ether (0.63 mL) at -78° C. under argon was added n-BuLi (1.6M in hexanes, 0.12 mL, 0.19 mmol) and the mixture was stirred at -78° C. (20 minutes). A solution of ethyl formate, 1M in ether (0.25 mmol, 2 eq.) was added and the mixture stirred (0.5 hours at -78° C.). Saturated aqueous NH4Cl (1 mL) was added and the mixture warmed to ambient temperature and extracted with ether (3×1 mL). The combined extracts were dried (MgSO4) and taken to dryness under reduced pressure, affording 43 mg of crude 28, however, contaminated with starting material 27.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:18][CH3:19])[CH2:8][CH2:7][CH:6]([CH:9]([NH:13][C:14](=[O:17])[CH:15]=[CH2:16])[CH2:10]C=C)[CH2:5][CH2:4]1.N1CCC1>ClCCCl>[CH3:19][O:18][C:3]1([O:2][CH3:1])[CH2:4][CH2:5][CH:6]([CH:9]2[NH:13][C:14](=[O:17])[CH:15]=[CH:16][CH2:10]2)[CH2:7][CH2:8]1
Reactant: C=CCC(NC(=O)C=C)C1CCC(OC)(OC)CC1
Agent: C1CNC1
Solvent: ClCCCl
Product: COC1(OC)CCC(C2CC=CC(=O)N2)CC1
Temperature: 50 °C

Procedure:
A solution of N-(1-(4,4-dimethoxycyclohexyl)but-3-en-1-yl)acrylamide (512 mg, 2.4 mmol), prepared in the previous step, and the Grubbs Generation II catalyst (97 mg, 0.11 mmol) in DCE (100 mL) was degassed and heated to 50° C. under argon for 2 hours. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (silica gel, DCM->0-5% MeOH/ethyl acetate) to afford the product.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[S:15][CH:16]=[CH:17][C:18]=1[C:19]#[N:20].[H-].[Na+]>C1COCC1>[F:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([NH:13][C:14]2[S:15][CH:16]=[CH:17][C:18]=2[C:19]#[N:20])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: N#Cc1ccsc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccsc1Nc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.6 %

Procedure:
Combine 2,4,5-trifluoro-nitrobenzene (5.00 g, 24.24 mmol), 2-aminothiophene-3-carbonitrile (3.51 g, 28.24 mmol), and anhydrous THF (30.0 ml). Cool the mixture to 10° and then slowly add NaH (2.26 g, 56.47 mmol, 60% dispersion in mineral oil) while keeping the temperature less than 10°. Warm the mixture to ambient temperature after NaH addition is complete. Stir the mixture at ambient temperature for 24 hours and then pour it onto ice chips. Extract the aqueous with ethyl acetate and then wash (brine), dry (sodium sulfate), and reduce the organic to residue. Purify the residue on silica gel using hexanes/dichloromethane (35:65) to give 4.06 g (51%) of the title compound as a red solid: mass spectrum (ion spray): m/z=280.0 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].F[C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=1>>[CH3:17][C:16]1[C:11]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#Cc1cccc(O)c1
Reactant: Cc1cccnc1F
Product: Cc1cccnc1Oc1cccc(C#N)c1

Procedure:
3-Hydroxy-benzonitrile was reacted with 2-fluoro-3-methylpyridine according to the method of Example 78A to provide the title compound. MS (DCI/NH3) m/z 211 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=[CH2:32].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC#N>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:32]=[CH:31][C:30]([O:34][CH3:35])=[O:33])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C=Cc1cccnc1
Temperature: 100 °C
Yield: 97 %

Procedure:
A mixture of 3-bromopyridine (4.82 mL, 0.05 mol), palladium acetate (0.22 g, 0.02 equiv.), tri-(o-tolyl)-phosphine (0.61 g, 0.04 equiv.), methyl acrylate (9.01 mL, 2 equiv.), triethylamine (12.5 mL) and CH3CN (25 mL) was sealed in a bomb and heated to 100° C. for 3.5 hours. The mixture was cooled in an ice-bath, the bomb was vented and the reaction mixture was concentrated in vacuo. The residue was extracted with 0.5N HCl/Et2O (3×), the organic layer was backwashed with additional 0.5N HCl and the aqueous layers were combined, basified with saturated NaHCO3 and extracted with ether. The ether layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 7.89 g (97%) of methyl 3-(3-pyridyl)-2-propenoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH:17]=[CH2:18].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(C#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:21]([O:20][C:16](=[O:19])/[CH:17]=[CH:18]/[C:2]1[CH:7]=[N:6][C:5]([NH2:8])=[C:4]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Nc1ncc(Br)cc1CN1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1cnc(N)c(CN2CCCCC2)c1
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
A solution of 5-bromo-3-piperidin-1-ylmethyl-pyridin-2-ylamine (500 mg, 1.85 mmol), tert-butyl acrylate (0.3 mL, 2.0 mmol), (i-Pr)2EtN (0.5 mL, 2.8 mmol) and P(o-tol)3 (114 mg, 0.37 mmol) in EtCN (10 mL) was de-oxygenated with argon for 30 min. Pd(OAc)2 (43 mg, 0.19 mmol) was added, and the mixture was de-oxygenated for 15 min. The mixture was heated to reflux for 18 h and then allowed to cool. The solvent was removed in vacuo. The residue was partitioned between EtOAc and H2O. The organic layer was washed with H2O and satd NaCl, dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, CH2Cl2 to 96:4 CH2Cl2/CH3OH) gave the title compound (350 mg, 60%) as a yellow solid: MS (ESI) m/e 318 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[NH2:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:8]=1[OH:16].C(OC1C=CC=C(N)C=1N)(C)C>>[CH3:5][O:4][CH2:3][CH2:2][O:16][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([NH2:13])[C:7]=1[NH2:6]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: COCCBr
Agent: CC(C)Oc1cccc(N)c1N
Product: COCCOc1cccc(N)c1N

Procedure:
Prepared from 1-bromo-2-methoxyethan and 2-amino-3-nitrophenol in analogy to 3-isopropoxy-benzene-1,2-diamine.