Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:12]([CH3:15])([O-:14])=[O:13].[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:15][N+:12]([O-:14])=[O:13]
Reactant: COc1ccc(C=O)c(F)c1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C=C[N+](=O)[O-])c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-Fluoro-4-methoxy-benzaldehyde (1 equivalent) was dissolved in MeOH and chilled in an ice bath. Nitromethane (1 equivalent) was added. NaOH (1.05 equivalents) in water was added dropwise to the nitromethane/aldehyde solution, such that the temperature did not rise above 15° C. The reaction was then allowed to stir at 0° C. for 15 minutes. The reaction mixture was poured into concentrated HCl diluted with water. Product was extracted with EtOAc and washed with water, brine, and dried (Na2SO4). Solvent was removed to yield a yellow oil which was freeze-dried in 90% MeCN/H2O to give the product 2-fluoro-4-methoxy-1-(2-nitro-vinyl)-benzene, which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:17][C:16]=2[O:30][CH2:31][CH2:32]Cl)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].[H-].[Na+].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][C:18]([S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:23])=[O:22])=[CH:17][C:16]=3[O:30][CH2:31][CH2:32]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(=O)(=O)c3ccccc3)cc2OCCCl)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCOc3cc(S(=O)(=O)c4ccccc4)ccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
To a solution of 4-[4-benzenesulfonyl-2-(2-chloro-ethoxy)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (0.175 g, 0.354 mmol) in 0.500 mL anhydrous DMF was added sodium iodide (2.0 mg, cat) followed by sodium hydride (17 mg. of a 60% dispersion in mineral oil, 0.424 mmol) in 3 portions. The reaction mixture was stirred at room temperature for 2 hours, added to 50 mL water, and then extracted twice with 50 mL ethyl acetate. The organic fraction was washed with 50 mL brine, dried over sodium sulfate, then concentrated in vacuo. The resulting crude oil was purified by flash chromatography (10%-40% ethyl acetate in hexanes) to give 0.111 g (0.242 mmol, 68%) of 4-(7-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C(OC(=O)C1C=CC(N[C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26](F)[C:27](F)=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=CC=1)C.ClC1C=CC(C2N(C(C3CCCCC3)C(O)=O)C3C=CC=CC=3N=2)=CC=1.[CH3:66][O:67][C:68](=[O:80])[C:69]1[CH:74]=[CH:73][C:72]([NH2:75])=[C:71]([C:76]([F:79])([F:78])[F:77])[CH:70]=1>>[CH3:66][O:67][C:68](=[O:80])[C:69]1[CH:74]=[CH:73][C:72]([NH:75][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:71]([C:76]([F:78])([F:77])[F:79])[CH:70]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Reactant: COC(=O)c1ccc(N)c(C(F)(F)F)c1
Agent: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2ccccc21
Product: COC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3ccccc32)c(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 22, intermediate d), from [2-(4-chloro-phenyl)-benzoimidazol-1-yl]-cyclohexyl-acetic acid (Ex. 39/40, int. b) and 4-amino-3-trifluoromethyl-benzoic acid methyl ester to give the product as a light yellow solid (57%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][O:10]2)=[CH:5][CH:4]=1.[N:20]1([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:14]1([C:9]2([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:23]4[CH2:22][CH2:21][N:20]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:24]4)=[CH:4][CH:5]=3)[O:13][CH2:12][CH2:11][O:10]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccc(C2(c3ccccc3)OCCO2)cc1
Reactant: CCOC(=O)CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CN1CCN(Cc2ccc(C3(c4ccccc4)OCCO3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a round-bottom flask were added 13 (2.57 g, 8.05 mmol, 1.0 equiv.), 10 (2.09 g, 12.1 mmol, 1.5 equiv.), K2CO3 (3.35 g, 24.2 mmol, 3.0 equiv.), and acetone (40 mL, 0.2 M). The reaction mixture was stirred overnight at reflux. The reaction mixture was cooled to room temperature. The solid was filtered and washed with acetone. The filtrate was concentrated and purified by silica gel column chromatography (gradient, 50-100% EtOAc/hexanes) to yield 14 (2.54 g, 77%) as a yellow oil. 1H-NMR (500 MHz, CDCl3) δ 7.52-7.50 (m, 2H), 7.44 (d, 2H, J=8.5 Hz), 7.34-7.25 (m, 5H), 4.17 (q, 2H, J=7.0 Hz), 4.09-4.06 (m, 2H), 4.05-4.02 (m, 2H), 2.57 (br s, 4H), 2.50 (br s, 4H), 1.26 (t, 3H, J=7.0 Hz). 13C-NMR (125 MHz, CDCl3): δ 170.3, 142.1, 140.9, 137.9, 128.9, 128.1, 128.0, 126.1, 126.0, 109.4, 64.8, 62.6, 60.6, 59.5, 53.1, 52.7, 14.2.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([CH:15]([CH3:17])[CH3:16])[C:5]2=[O:18].[NH2:19]C(N)=O>>[NH2:19][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([CH:15]([CH3:17])[CH3:16])[C:5]2=[O:18]
Reactant: CC(C)N1C(=O)c2cc(Cl)c([N+](=O)[O-])cc2C1=O
Reactant: NC(N)=O
Product: CC(C)N1C(=O)c2cc(N)c([N+](=O)[O-])cc2C1=O
Temperature: 150 °C

Procedure:
5-Chloro-2-isopropyl-6-nitroisoindoline-1,3-dione (14.40 g, 59.85 mmol) and urea (35.95 g, 599 mmol) were mixed together under argon. The mixture was stirred and heated to 150° C. for 3 h and cooled to rt. The solid was washed with 200 mL of hot water (90° C.) and filtered to remove the remaining urea. The isolated yellow solid was washed twice with hot water, dried under vacuum and purified by column chromatography (silica-gel CH2Cl2/acetone=19/1 v/v) to give a solid product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[F:15][C:16]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:17]=1[NH2:18]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:18][C:17]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:16]=2[F:15])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: Nc1cc(F)ccc1F
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Nc2cc(F)ccc2F)cc1

Procedure:
First, p-toluic acid is converted to an acid chloride with thionyl chloride. The acid chloride is reacted with 2,5-difluoroaniline to form 4-methyl-2',5'-difluorobenzanilide (V). The compound (V) is then reacted with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphethane-2,4-disulfide (Lawesson's reagent) to form 4-methyl-2',5'-difluorobenzothioanilide (VI) which is then reacted with potassium tert-butoxide to form 2-(4-methylphenyl)-5-fluorobenzothiazole (VII). The compound (VII) is then reacted with a halogenating agent such as N-bromosuccinimide, N-chlorosuccinimide or bromine to form a compound (VIII). Finally, the compound (VIII) is reacted with an excess of triethyl phosphite to produce the compound of formula (IV)-1 in which Y is a fluorine atom.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][O:12][C:8]=2[C:7]=1[CH2:19][CH2:20][CH3:21].BrC(Cl)CC.[C:27]1([CH:33]2[CH2:38][NH:37][C:36](=[O:39])[NH:35][C:34]2=[O:40])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:27]1([CH:33]2[CH2:38][NH:37][C:36](=[O:39])[N:35]([CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:18]=[CH:17][C:9]4[C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][O:12][C:8]=4[C:7]=3[CH2:19][CH2:20][CH3:21])[C:34]2=[O:40])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C1NCC(c2ccccc2)C(=O)N1
Reactant: CCCc1c(OCCCCl)ccc2c(C(F)(F)F)noc12
Agent: CCC(Cl)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCN2C(=O)NCC(c3ccccc3)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
A mixture of 6-(3-chloropropoxy)-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole, prepared as for Example 7 from bromochloropropane, (36 mg, 0.12 mmol), 5-phenyldihydropyrimidine-2,4(1H,3H)-dione, from this Example step 1, (42.5 mg, 0.22 mmol), Cs2CO3 (145.7 mg, 0.45 mmol) and KI (9.3 mg, 0.056 mmol) in dry DMF was stirred at room temperature overnight. The reaction mixture was diluted with water and partitioned between ethyl acetate and water. Combined organic extracts were washed with water and brine, dried over Na2SO4 and the solvent evaporated in vacuo. The product was purified by HPLC using 30% to 70% gradient CH3CN:H2O).
Reaction SMILES: I/[CH:2]=[CH:3]/[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[NH:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]I>[C:8]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:10][C:5]([O:4]/[CH:3]=[CH:2]/[N:17]2[CH:21]=[CH:20][CH:19]=[CH:18]2)=[CH:6][CH:7]=1
Reactant: I/C=C/Oc1ccc(-c2ccccc2)cc1
Reactant: c1cc[nH]c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C(=C/n1cccc1)\Oc1ccc(-c2ccccc2)cc1
Yield: 86.4 %

Procedure:
The compound 10 was prepared following the procedure described for 5 with 4 (0.2 g, 0.62 mmol, 1 eq), pyrrole (0.062 g, 0.93 mmol, 1.5 eq), Cs2CO3 (0.40 g, 1.2 mmol, 2.5 eq), CuI (0.059 g, 0.31 mmol, 0.5 eq) and L2 (0.060 g, 0.31 mmol, 0.5 eq) at 70° C. for 12 h to give crude product which were purified by silica gel column chromatography using ethyl acetate-hexane (9:95) to afford compound 10 as white crystals (0.14 g, 85%): mp 102-105° C. Olefinic protons coupling on the named compound gave an AB-system with a typical roof effect with peaks centered at 7.04 and 6.99 ppm. 1H NMR (300 MHz, CDCl3): 7.62-7.53 (m, 4H, HAr), 7.48-7.40 (m, 2H, HAr), 7.38-7.31 (m, 1H, HAr), 7.17-7.09 (m, 2H, HAr), 7.04 (distorted d, 1H, J=11.1 Hz, (O)—CH═CH(N)), 6.99 (distorted d, 1H, J=11.1 Hz, (O)—CH═CH(N)), 6.82 (dd, 2H, J1=4.2 Hz, J2=2.2 Hz, CH═CH of pyrrole), 6.28 (dd, 2H, J1=4.2 Hz, J2=2.2 Hz, CH═CH); 13C NMR (75 MHz, CDCl3): 156.8, 140.4, 136.3, 135.0, 128.8, 128.4, 127.1, 126.9, 119.6, 118.3, 116.5, 110.0 ppm; IR (cm−1): 3086, 3034, 2715, 2682, 1659, 1607, 1587, 1517, 1485, 1360, 1326, 1300, 1239, 1229, 1185, 1173, 1119, 1094, 1072, 1056, 1007, 975, 907, 857, 838, 614; HRMS (ESI) Calculated for C18H15NO [M+H]+ 262.1232. Found 262.1233; Elemental analysis calculated for C18H15NO.0.17H2O: C, 81.77; H, 5.85; N, 5.29. found: C, 81.76; H, 5.91; N, 5.03.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:31]([C:27]2[O:26][CH:30]=[CH:29][CH:28]=2)=[O:32])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccco1
Reactant: CC(C)C[C@H](N)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Product: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)NCCCCc1ccccc1)NC(=O)c1ccco1
Yield: 19 %

Procedure:
Using the procedure described in Example 7, treatment of 1-[2-(S)-amino-4-methylpentyl]-L-proline 4phenylbutylamide (125 mg) with 2-furoyl chloride (50 uL) provided 27 mg (19%) of the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[NH:20]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][Cl:30]>>[Cl:30][CH2:29][CH2:28][CH2:27][N:20]1[C:19]([O:23][CH3:24])=[N:18][C:17]2[C:21]1=[N:22][C:14]([O:13][C@@H:9]([CH3:8])[CH2:10][CH2:11][CH3:12])=[N:15][C:16]=2[NH2:25]
Reactant: ClCCCBr
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 44 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and 1-bromo-3-chloropropane.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[NH:10][C:11]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:18]([O:20]C)=[O:19])=[C:12]([CH3:14])[N:13]=2)[CH2:5][CH2:4]1.[OH-].[Na+]>CO.O>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[NH:10][C:11]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:18]([OH:20])=[O:19])=[C:12]([CH3:14])[N:13]=2)[CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(C3CCC(OC)CC3)nc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC1CCC(c2nc(C)c(-c3cc(C(=O)O)ccc3C)[nH]2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(2-(4-methoxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 300.2, 150 mg, 0.44 mmol) in methanol (4 mL). A solution of NaOH (70 mg, 1.75 mmol) in water (2 mL) was added to the reaction. The reaction mixture was stirred for 3 h at 50° C., then concentrated under reduced pressure. The reaction mixture was diluted with 2 mL of water. The pH of the solution was adjusted to 1 with HCl (2 M) and concentrated under reduced pressure. This resulted in 240 mg (crude) of the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:32]=1[CH2:33]Br>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH2:33][C:32]3[C:31]([Cl:30])=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:39])=[CH:18][CH:19]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: Nc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Clc1cccc(Cl)c1CNc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A mixture of 4-(4-benzyl-morpholin-2-yl)-phenylamine (0.82 g; 3.06 mmol), DIPEA (1.57 mL; 9.17 mmol) and 2,6-dichlorobenzyl bromide (0.88 g; 3.67 mmol) in MeOH (25 mL). was stirred at RT, overnight. The resulting mixture was partitioned between 5% aqueous NaHCO3 and EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to afford [4-(4-benzyl-morpholin-2-yl)-phenyl]-(2,6-dichloro-benzyl)-amine (1.25 g).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][CH:10]=[C:11]([CH2:12]N(C)C)[C:5]=2[CH:4]=1.[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[Na].Cl>>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([CH2:12][C:11]1[C:5]2[C:6](=[CH:7][CH:8]=[C:3]([CH2:2][CH3:1])[CH:4]=2)[NH:9][CH:10]=1)[C:16]([O:24][CH2:25][CH3:26])=[O:23])[CH3:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCc1ccc2[nH]cc(CN(C)C)c2c1
Agent: Cl
Agent: [Na]
Product: CCOC(=O)C(Cc1c[nH]c2ccc(CC)cc12)C(=O)OCC
Temperature: 120 °C
Reaction time: 24 h
Yield: 85.1 %

Procedure:
The 5-Ethylgramine (1.25 g, 6.18 mmol) was combined with diethyl malonate (2.85 mL, 18.54 mmol) and heated to 120° C. until a homogeneous solution was formed. To this mixture was added sodium metal (100 mg, 4.36 mmol) and the mixture was stirred at 120° C. for 24 hours. TLC indicated the completion of the reaction. The reaction was allowed to cool to room temperature and a solution of 5% HCl (aqueous) was slowly added to the mixture and the resulting product was extracted with EtOAc. The organic layer was washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulafate, filtered and evaporated to give compound 12 as a white solid (1.67 g; 85% yield; M+1=318.4). The product was taken into the next step without purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[C:7]1[CH2:12][CH2:11][CH2:10][NH:9][C:8]1=[O:13].CO>[Ir].ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][C:8]1=[O:13]
Reactant: O=C1NCCCC1=Cc1ccco1
Agent: [Ir]
Solvent: CO
Solvent: ClCCl
Product: O=C1NCCCC1Cc1ccco1
Yield: 91.7 %

Procedure:
This example describes the preparation of I where n=2 and R1=2-furanyl. In a nitrogen-filled glove box, a Fisher-Porter tube was charged with iridium catalyst prepared as in Example 1 (10 mg, 0.012 mmol) and 3-(2-furanylmethylidene)-2-piperidone (250 mg, 1.4 mmol). Methanol (3 mL) and dichloromethane (3 mL) were added and the system was flushed 4 times with hydrogen and pressured to 60 psi (0.5 MPa) H2. After 18 h the reaction mixture was filtered through a short pad of silica. The solvent was removed at reduced pressure to afford 3-(2-furanylmethyl)-2-piperidone (230 mg, 92%) as a white crystalline solid. Chiral HPLC analysis (Chiralpak AD, 85% heptane, 15% ethanol, 30° C.) indicated that conversion was 100% and the enantiomeric excess was 95%. 13C NMR: δ 21.55, 26.12, 29.99, 40.91, 42.57, 106.80, 110.39, 141.38, 153.99, 174.20; 1H NMR: δ 1.49 (m, 1H), 1.68 (m, 1H), 1.75-1.91 (m, 2H), 2.62 (m, 1H), 2.82 (m, 1H), 3.29 (m, 3H), 6.06 (m, 1H), 6.29 (m, 1H), 7.29 (m, 1H), 7.34 (br s, 1H).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH3:16])[C:6](=[O:17])[C:5]=1[NH2:18])(=[O:3])[CH3:2].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[C:1]([C:4]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]([CH3:16])[C:6](=[O:17])[C:5]=1[NH:18][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(-c2ccccc2)nn(C)c(=O)c1N
Reactant: OB(O)c1cccc(F)c1
Product: CC(=O)c1c(-c2ccccc2)nn(C)c(=O)c1Nc1cccc(F)c1

Procedure:
The title compound was synthesized from 5-acetyl-4-amino-2-methyl-6-phenylpyridazin-3(2H)-one (Dal Piaz, V., Ciciani, G, Giovannoni, M. P., Heterocycles, 1991, 32, 1173-9) and the corresponding 3-fluorophenylboronic acid following the procedure of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[S:11]3)=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[N+:20]([O-:22])=[O:21])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[S:11]3)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2cn3c(n2)sc2ccccc23)cc1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1c(-c2ccc(Cl)cc2)nc2sc3ccccc3n12
Temperature: 0 °C

Procedure:
After cooling 30 ml of fuming nitric acid to -35° to -45° C., 3 g of 2-(p-chlorophenyl)imidazo[2,1-b]benzothiazole was gradually added thereto. The reaction mixture was poured into ice water and the crystals which formed were recovered by filtration and recrystallized from acetic acid to provide 2.2 g of 2-(p-chlorophenyl)-3-nitroimidazo[2,1-b]benzothiazole.
Reaction SMILES: Cl.[OH:2][C@@H:3]1[C@H:8]([OH:9])[C@@H:7]([O:10][CH3:11])[C:6]([CH3:13])([CH3:12])[O:5][C@H:4]1[O:14][C:15]1[C:24]([CH3:25])=[C:23]2[C:18]([CH:19]=[C:20]([NH:27][C:28]([C:30]3[CH:31]=[C:32]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4C)[C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:29])[C:21](=[O:26])[O:22]2)=[CH:17][CH:16]=1.[H-].[Na+].[CH:47]1C=CC(CBr)=CC=1>CO>[OH:2][C@@H:3]1[C@H:8]([OH:9])[C@@H:7]([O:10][CH3:11])[C:6]([CH3:13])([CH3:12])[O:5][C@H:4]1[O:14][C:15]1[C:24]([CH3:25])=[C:23]2[C:18]([CH:19]=[C:20]([NH:27][C:28]([C:30]3[CH:31]=[C:32]([C:38]4[CH:39]=[CH:40][CH:41]=[C:42]([CH3:47])[CH:43]=4)[C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:29])[C:21](=[O:26])[O:22]2)=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C(=O)Nc2cc3ccc(O[C@@H]4OC(C)(C)[C@H](OC)[C@@H](O)[C@H]4O)c(C)c3oc2=O)cc1-c1ccccc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(=O)Nc2cc3ccc(O[C@@H]4OC(C)(C)[C@H](OC)[C@@H](O)[C@H]4O)c(C)c3oc2=O)cc1-c1cccc(C)c1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
Hydrogen chloride was bubbled through 29 (2.00 g, 6.16 mmol) in anhydrous MeOH (44.0 mL) for 3 minutes at room temperature, then the solution was stirred at 50° C. for 5 minutes. The solvent was concentrated and the residue placed under high vacuum for 6 hours to ensure complete removal of MeOH. The yellow residue was dissolved in anhydrous dimethylformamide (44.0 mL) and cooled to 0° C., then NaH (997 mg, 24.93 mmol) was added. After 15 minutes, BnBr (1.20 mL, 1.73 g, 10.09 mmol) was added and the reaction was warmed to room temperature over 18 hours. Reaction contents were partitioned between saturated aqueous NaHCO3 (500 mL) and EtOAc (500 mL), then extracted with EtOAc (3×500 mL). The combined organic layers were washed with water (3×1 L), saturated aqueous NaCl solution (1 L), dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 9:1 Hexanes:EtOAc) to give 30 as a light orange solid containing greater than 80% 3-bromo isomer (1.70 g, 88%), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][N:5]=[C:6]([S:9][CH3:10])[S:7][CH3:8].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CN(C)C=O>[CH3:10][S:9][C:6](=[N:5][C:4](=[CH:14][N:15]([CH3:17])[CH3:16])[C:3]([O:2][CH3:1])=[O:11])[S:7][CH3:8]
Reactant: COC(=O)CN=C(SC)SC
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(=CN(C)C)N=C(SC)SC

Procedure:
Commercially available N-[Bis(methylthio)methylene]glycine methyl ester (5.06 g, 26.18 mmol) and N,N-Dimethylformamide dimethyl acetal (4.03 g, 31.41 mmol) were dissolved in N,N-dimethylformamide (10 mL) and heated to reflux under nitrogen for 4.5 h. The solvent was removed under reduced pressure and the product solidified (6.44 g, 99%) after storage at room temperature under high vacuum over night. 1H NMR (CDCl3, 400 MHz): δ 6.96 (s, 1H); 3.68 (s, 3H); 2.95 (s, 6H); 2.53 (s, 3H); 2.49 (s, 3H).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([CH2:14][CH2:13]2)[C:5]1=[O:15].C([O-])(=O)C.[Na+].C(O)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Br:1][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH3:3])[C:5](=[O:15])[C:6]12[CH2:14][CH2:13]1
Reactant: CN1C(=O)C2(CC2)c2ccccc21
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1C(=O)C2(CC2)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
Add bromine (1.4 g, 8.7 mmol) dropwise to the mixture of 1′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (1.5 g, 8.7 mmol), sodium acetate (0.7 g, 8.7 mmol) and acetic acid (0.52 g, 8.7 mmol) in dichloromethane (15 mL) at 0° C. After addition, stir the resulting mixture at room temperature overnight. Pour the reaction mixture to the cold sodium thiosulfate solution, extract with ethyl acetate (100 mL×2), combine the organic layers, and wash with brine (20 mL), dry over anhydrous sodium sulfate. Concentrate the solution under reduced pressure to give the crude product, purify by flash chromatography (silica gel, EtOAc:PE=1:5) to afford the title compound (1.0 g, 47.6%). MS: (M+1): 254.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.CN([CH:28]=[O:29])C>>[C:1]1([C:7]2[N:8]=[C:9]([CH:28]=[O:29])[N:10]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccccc2)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: C[Si](C)(C)CCOCn1cc(-c2ccccc2)nc1C=O
Yield: 97.8 %

Procedure:
Reaction of 4-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (380 mg, 1.39 mmol), 2.5 M n-BuLi (720 uL, 1.80 mmol), and DMF (323 uL, 4.17 mmol) for 4 h at −40° C. gave the title compound (411 mg, 98%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.93 (t, 2H, J=9.0 Hz), 3.61 (t, 2H, J=9.0 Hz), 5.83 (s, 2H), 7.26-7.46 (m, 3H), 7.65 (s, 1H), 7.83 (d, 2H, J=9.0 Hz), 9.89 (s, 1H).