Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5](=[O:13])[N:6]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:7]=1.[N:15]1([C:21](=[O:24])[CH:22]=[CH2:23])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[C:21]([N:15]1[CH2:20][CH2:19][N:18]([C:10](=[O:12])[CH2:9][CH2:8][N:6]2[CH:7]=[C:2]([Br:1])[C:3]([CH3:14])=[CH:4][C:5]2=[O:13])[CH2:17][CH2:16]1)(=[O:24])[CH:22]=[CH2:23]
Reactant: Cc1cc(=O)n(CCC(=O)O)cc1Br
Reactant: C=CC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(=O)N1CCN(C(=O)CCn2cc(Br)c(C)cc2=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.9 %

Procedure:
A mixture of 3-(5-Bromo-4-methyl-2-oxopyridin-1(2H)-yl)propanoic acid (112 mg, 0.43 mmol), 1-(piperazin-1-yl)prop-2-en-1-one (80 mg, 0.43 mmol), HATU (163 mg, 0.43 mmol) and Et3N (0.2 mL, 1.43 mmol) in DMF (5 mL) was stirred at room temperature for 2 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via Isolera One (silica cartridge, 0-6% MeOH/DCM) to afford the desired product (22.8 mg, 14 yield). 1H NMR (300 MHz, CDCl3) δ: 7.73 (s, 1H), 6.55 (dd, J=10.5, 16.7 Hz, 1H), 6.46 (s, 1H), 6.32 (dd, J=1.8, 16.8 Hz, 1H), 5.75 (dd, J=1.8, 10.5 Hz, 1H), 4.20 (t, J=6.0 Hz, 2H), 3.4-3.6 (m, 8H), 2.86 (t, J=6.0 Hz, 2H), 2.22 (s, 3H). ESI-MS m/z: 382.05 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[H-].[Na+].[CH2:10](Br)[CH:11]=[CH2:12]>CN(C=O)C>[CH2:12]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7])[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCCCC1=O

Procedure:
2-Piperidinone is deprotonated with NaH in DMF solution and reaction with allyl bromide, and 1-allyl-2-piperidinone is obtained by distillation. Ozonolysis in MeOH solution at -78° C., followed by reductive workup with Me2S, gives the aldehyde derivative, which is reductively aminated using diethylamine hydrochloride and NaBH4 to give the title compound.
Reaction SMILES: C[Al](C)C.[N:5]([Si](C)(C)C)=[N+:6]=[N-:7].[Si:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:29]3[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:28]=3[N:27]=2)=[CH:22][CH:21]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[N:30]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)[C:29]3[CH:37]=[CH:38][C:39]([C:41]4[NH:7][N:6]=[N:5][N:42]=4)=[CH:40][C:28]=3[N:27]=2)=[CH:24][CH:25]=1)([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(C#N)ccc3n2C2CCCCC2)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(-c4nnn[nH]4)ccc3n2C2CCCCC2)cc1
Temperature: 95 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
Trimethylaluminum (20 mL of a 2.0 M solution in toluene, 0.040 mol) was added to a dry flask. Azidotrimethylsilane (5.3 mL, 0.040 mol) and compound 20 were added. The solution was stirred for 18 h at an oil bath temperature of 95° C. The solution was cooled and poured into a mixture of ethyl acetate and ice. The mixture was carefully acidified with dilute hydrochloric acid (caution-done in hood, hydrazoic acid liberated) to precipitate compound 21. The compound was crystallized from ethyl acetate—hexanes to afford 21 as a pinkish solid (4.13 g, 87%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:15](=[NH:16])[N:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]3=[N:12][C:11]=2[S:21][CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)Cl>[C:1]1([S:7]([C:10]2[C:15](=[NH:16])[N:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]3=[N:12][C:11]=2[S:21]([CH3:22])=[O:28])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccccn2c(=N)c1S(=O)(=O)c1ccccc1
Solvent: ClCCl
Product: CS(=O)c1nc2ccccn2c(=N)c1S(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 68 %

Procedure:
3-Benzenesulfonyl-2-methylsulfanyl-pyrido[1,2-a]pyrimidin-4-ylideneamine (50 mg, 0.15 mmol) was dissolved in anhydrous methylenechloride (2 ml) to which 3-chloroperoxybenzoic acid powder (32 mg, 50-60%, ˜0.11 mmol) was added at 0° C. and stirred for 2 hours. In order to neutralize the reaction mixture, 2,6-tert-butyl-4-methylpyridine (38 mg, 90%, 0.17 mmol) was added. After concentration, the crude mixture was purified by preparative HPLC (XTerra™ MS C18 5.0 mM, MeOH/H2O as the eluent) to yield 26 mg of product as a pale yellow solid.
Reaction SMILES: C[Al](C)C.[CH2:5]([NH2:8])[CH2:6][NH2:7].CO[C:11]([C:13]1[N:14]=[N:15][N:16]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.O>C1(C)C=CC=CC=1>[F:36][C:35]([F:37])([F:38])[C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=1)[CH2:24][N:16]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:13]([C:11]2[NH:7][CH2:6][CH2:5][N:8]=2)[N:14]=[N:15]1
Reactant: COC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Reactant: NCCN
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1cc(Cn2nnc(C3=NCCN3)c2-c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 19 %

Procedure:
To a solution of Me3Al (1.36 mL, 2M soln in toluene) at 0° C. under N2, add ethylenediamine (185 μL, 0.36 mmol) and stir for several minutes warming to RT. Add 1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylic acid methyl ester (750 mg, 1.69 mmol) dissolved in toluene to this solution. Reflux reaction for 3.5 hours at 110° C. Cool to RT and stir for 12 hours. Quench reaction with MeOH (2 mL), add H2O (2 mL) and extract with CH2Cl2 (4 mL×2). Dry over Na2SO4 and concentrate to afford title compound (30 mg, 4%). MS (IS) 440.1 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)O)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].CN(C)C1C=CC=CC=1.S(Br)([Br:40])=O>C(Cl)(Cl)Cl>[CH3:8][C@@H:7]([C@@H:9]1[C@@:27]2([CH3:28])[CH2:26][CH2:25][C@@H:24]3[C@@:22]4([CH3:23])[CH2:21][CH2:20][C@H:18]([Br:40])[CH2:17][C:16]4=[CH:15][CH2:14][C@H:13]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=S(Br)Br
Solvent: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](Br)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Cholesterol, (25 g, 64.6 mmol) was dissolved in 10 ml of dimethylaniline (78.9 mmol) and 5 ml of chloroform. While stirring on ice; small quantities of thionyl bromide (6 ml, 77.6 mmol) dissolved in 20 ml of cold chloroform was added slowly over a period of 15 minutes. After the addition of thionyl bromide was complete, the mixture was stirred for an additional 2 hours at room temperature. The resulting solution was poured into 200 ml of ice cold 95% ethanol and left on ice for 2 hour until crystallization was complete. The product was filtered and washed with 25 ml of ice cold 95% ethanol. A small amount of product was recovered from the filtrate with the addition of 75 ml distilled water followed by refrigeration. Finally, the product was recrystallized from 120 ml of acetone giving 21.8 g of cholesteryl bromide (yield, 75%) with a melting point of 93-95° C. (lit 97-98° C.). The identity of the product was confirmed with mass spectrometry (EI) which showed an intense peak with an m/z of 448, corresponding to the molecular ion (M+°) of cholesteryl bromide. Also, the bromide molecular weight pattern characteristic of the two different isotopes of bromine (79Br:81-Br,1:1) was observed.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:5]2[N:6]([C:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[C:13]([CH3:20])[CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1.F[P-](F)(F)(F)(F)F.CN([C+](N(C)C)N1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[Br:1][C:2]1[N:3]=[C:4]([NH:21][CH2:22][CH:23]([CH3:24])[CH3:25])[C:5]2[N:6]([C:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([NH:29][CH:26]4[CH2:28][CH2:27]4)=[O:16])=[C:13]([CH3:20])[CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: NC1CC1
Reactant: Cc1cc(-c2cnc3c(NCC(C)C)nc(Br)cn23)ccc1C(=O)O
Agent: CN(C)[C+](N(C)C)n1n[n+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2cnc3c(NCC(C)C)nc(Br)cn23)ccc1C(=O)NC1CC1
Temperature: 23 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
To a solution of 411 mg (1 mmol) 4-(6-Bromo-8-isobutylamino-imidazo[1,2-a]pyrazin-3-yl)-2-methyl-benzoic acid which was prepared according to intermediate example 49b in 4 mL 1-methylpyrrolidin-2-one were added 114.9 mg cyclopropanamine, 760 mg bis(dimethylamino)(3-oxido-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)methylium hexafluorophosphate and 685 μL N-ethyl-N-isopropylpropan-2-amine and the mixture was stirred overnight at 23° C. After filtration and removal of the solvent the residue was purified by chromatography to give 65.5 mg (15%) of the title compound.
Reaction SMILES: [Br:1][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)(F)F)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.BrC1C=C[C:30]2[C:31]3[N:32]=C(C(N)=O)SC=3CCO[C:29]=2[CH:28]=1.N1C=CC=CC=1CNN>>[Br:1][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]5[CH:28]=[CH:29][CH:30]=[CH:31][N:32]=5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: NNCc1ccccn1
Product: Brc1ccc2c(c1)OCCc1sc(-c3ncnn3Cc3ccccn3)nc1-2

Procedure:
Following the procedure for 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, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide 25 was reacted with Pyridin-2-ylmethyl-hydrazine to give 8-Bromo-2-(2-pyridin-2-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene. MS (ESI+) 440.0/442.0.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:11][C:12]4[C:17]([N:18]=3)=[CH:16][CH:15]=[C:14]([C:19]3([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:21][CH2:20]3)[N:13]=4)=[CH:7][CH:8]=2)[CH2:3][NH:2]1.C(N(C(C)C)CC)(C)C.Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>C(Cl)Cl>[C:22]1([C:19]2([C:14]3[N:13]=[C:12]4[S:11][C:10]([C:6]5[CH:5]=[C:4]6[C:9](=[CH:8][CH:7]=5)[CH2:1][N:2]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:3]6)=[N:18][C:17]4=[CH:16][CH:15]=3)[CH2:20][CH2:21]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)CBr
Reactant: c1ccc(C2(c3ccc4nc(-c5ccc6c(c5)CNC6)sc4n3)CC2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(Isoindolin-5-yl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (97 mg, 0.263 mmol) was dissolved in DCM (2.625 mL) and diisopropylethylamine (91 μL, 0.525 mmol) before methyl bromoacetate (48.5 μL, 0.525 mmol) was added and stirred at ambient temperature for 3 h. Methyl 2-(5-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)isoindolin-2-yl)acetate was obtained after purification via flash chromatograpy. MS (ESI) m/z: Calculated: 441.2; Observed: 442.4 (M++H).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)[C:5]1=[O:30])[CH:2]=C.I([O-])(=O)(=O)=[O:33].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:6]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][N:25]=3)[C:5](=[O:30])[C@:4]([CH2:1][CH:2]=[O:33])([CH3:31])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ccncn2)C1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@]1(CC=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ccncn2)C1=O
Reaction time: 0.08 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pyrimidin-4-yl)piperidin-2-one (Example 110, Step B) (60 mg, 0.13 mmol) in a mixture of tetrahydrofuran (2.7 mL) and water (880 μL) was added osmium tetroxide (1.7 mg, 6.6 μmol). After 5 minutes, sodium periodate (89 mg, 0.46 mmol) was added and the reaction mixture was stirred for 14 hours. The reaction mixture was filtered through Celite® (J. T. Baker, Phillipsberg, N.J., diatomaceous earth) and washed with EtOAc and water. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography (0 to 75% EtOAc/hexanes, gradient elution) provided the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-].[C:10]([O:13]C(=O)C)(=[O:12])[CH3:11]>>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH2:1][O:13][C:10](=[O:12])[CH3:11])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc[n+]([O-])c(C)c1
Product: CC(=O)OCc1cc(C)ccn1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 29.8 %

Procedure:
Acetic anhydride (30 mL) was added to 2,4-dimethyl-pyridine 1-oxide (1.93 g, 15.7 mmol) described in Manufacturing Example 11-1-1, and the mixture was stirred for 10 minutes at 110° C. The reaction solution was allowed to room temperature and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:2, then ethyl acetate) to obtain the title compound (774 mg, 29.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][NH2:24].[O:25]=[CH:26][CH2:27][C:28](O)=[O:29]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][N:24]=[C:28]([OH:29])[CH2:27][CH:26]=[O:25]
Reactant: CSc1ccc(/C=C2/C(C)=C(CCON)c3cc(F)ccc32)cc1
Reactant: O=CCC(=O)O
Product: CSc1ccc(/C=C2/C(C)=C(CCON=C(O)CC=O)c3cc(F)ccc32)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylthiophenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 3-oxopropionic acid by the method of Example 1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])/[C:8]/2=[CH:17]/OC)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]([C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)[C:25](=[O:34])[CH:24]=1.C(N(CC)CC)C>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])/[C:8]/2=[CH:17]\[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]([C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)[C:25](=[O:34])[CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(C(C)(C)C)cc21
Reactant: NCc1ccn(-c2ccoc2)c(=O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc2c(c1)/C(=C/NCc1ccn(-c3ccoc3)c(=O)c1)C(=O)NC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
A mixture of (4E)-6-tert-butyl-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (50 mg, 0.19 mmol), 4-aminomethyl-1-furan-3-yl-1H-pyridin-2-one hydrochloride (43 mg, 0.19 mmol), and triethylamine (150 μL, 1.1 mmol) in N,N-dimethylformamide (2 mL) is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure, and the residue is triturated with chloroform to provide (4Z)-6-tert-butyl-4-[({[1-(3-furyl)-2-oxo-1,2-dihydropyridin-4-yl]methyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione as a white solid (34 mg, 43%).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH2:6]([C:13]1[S:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.C(=S)=S>O>[CH2:6]([C:13]1[S:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[C:14]=1[C:22]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:31])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(Cc2cc3ccccc3s2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: S=C=S
Solvent: O
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)sc3ccccc23)cc1
Reaction time: 6 h
Yield: 81.8 %

Procedure:
Tin tetrachloride (9.0 mL, 76.91 mmol) was added dropwise over a 25 minute period to a stirred solution of 2-benzyl-benzo[b]thiophene (14.87 g, 96.79 mmol), p-anisoyl chloride (11.75 g, 68.87 mmol) and carbon disulfide (75 mL) under a dry nitrogen atmosphere. After 6 hours, the reaction mixture was added to water and extracted with dichloromethane. The dichloromethane extract was washed with sat. aq. sodium bicarbonate and brine. The solvent was removed and the resultant solid was triturated with pet. ether to give the title compound as a white solid (20.2 g, 85%): mp 135-137° C.: NMR (CDCl3); δ 7.85 (dm, J=9 Hz, 2H), 7.73 (dm, 1H), 7.42 (dm, 1H), 7.18-7.30 (m, 7H), 6.93 (dm, J=9 Hz, 2H), 4.21 (s, 2H, CH2), 3.88 (s, 3H, CH3): IR (KBr, cm-1): 1650; MS (EI): 358 (100%, MI), 343 (15%), 327 (75%); Anal. Calc. for C23H18O2S: C, 77.07, H, 5.06, N, 0.00. Found: C, 76.91, H, 5.02, N, -0.12.
Reaction SMILES: [OH:1][CH:2]([CH3:15])[CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([O:1][CH:2]([CH3:15])[CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])(=[O:25])[CH3:24]
Reactant: CC(O)CCC(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC(C)CCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
63 g (302.5 mmol) of benzyl 4-hydroxypentanoate and 46.4 ml (332.8 mmol) of triethylamine are charged under nitrogen at room temperature to 300 ml of CH2Cl2. The mixture is cooled to 0° C. and 21.5 ml (302.5 mmol) of acetyl chloride are added dropwise at 0°-5° C. When the dropwise addition is complete, the ice bath is removed and stirring is continued overnight at room temperature. The reaction mixture is mixed with ice-water and the organic phase is separated and washed twice with water. The aqueous phases are extracted twice with CH2Cl2. The organic phases are combined, dried over MgSO4, filtered and concentrated by evaporation. Distillation of the residue gives benzyl 4-acetoxypentanoate as a colourless oil of b.p. 126°-127° C./2.10-2 torr.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:9][CH:8]=1)(=[O:4])=[O:3].[C:23]1([CH3:41])[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=[C:31]([C:37]([F:40])([F:39])[F:38])[N:30]=2)[CH:24]=1>CN(C)C1C=CN=CC=1>[C:23]1([CH3:41])[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[C:34]([CH2:35][NH:36][C:14](=[O:22])[NH:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:12][CH:11]=3)=[CH:33][CH:32]=[C:31]([C:37]([F:39])([F:38])[F:40])[N:30]=2)[CH:24]=1
Reactant: CS(=O)(=O)NCc1ccc(NC(=O)Oc2ccccc2)cc1
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Agent: CN(C)c1ccncc1
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)Nc2ccc(CNS(C)(=O)=O)cc2)c1
Temperature: 50 °C

Procedure:
To a solution of phenyl 4-(methylsulfonamidomethyl)phenylcarbamate (59 mg, 0.18 mmol) acetonitrile (3 mL) was added 4-dimethylaminopyridine (23 mg, 0.18 mmol) and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (49 mg, 0.18 mmol) at room temperature. The reaction mixture was heated to 50° C. for 16 h. TLC showed complete consumption of starting material. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic part was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude was purified by column chromatography to N-(4-(3-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)ureido)benzyl)methanesulfonamide (example 2) (57 mg, 63%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=1.CS(C)=O.CC(C)([O-])C.[Na+]>O>[Cl:16][C:17]1[C:22]([O:15][CH:13]2[CH2:14][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:12]2)=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: O=C(OCc1ccccc1)N1CC(O)C1
Reactant: Clc1nccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CC(Oc2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
To a solution of 3-hydroxy-azetidine-1-carboxylic acid benzyl ester (5.19 g, 27.4 mmol, purchased from Ace Synthesis), 2,3-dichloropyrazine (4.116 g, 27.6 mmol, Oakwood) and DMSO (40 mL) was added sodium tert-butoxide (2.64 g, 27.4 mmol) in three portions. The solution was allowed to stir at room temperature. After 2 hours, the reaction was poured into water (200 mL) and the aqueous solution was extracted with ether (3×50 mL). The combined ether layers were washed with water (50 mL), brine (50 mL), and then concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (80 g), eluting with 0% to 20% EtOAc in hexane, to provide benzyl 3-(3-chloropyrazin-2-yloxy)azetidine-1-carboxylate (5.4 g, 61.6% yield), as a yellow oil. MS (ESI) m/z 320.1 (MH+). ICSO (uM): 1.33.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[N+]([O-])=O)\[CH3:10])=[CH:4][CH:3]=1.[N+:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])#[C-:15]>CC(O)C.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:10])=[CH:15][NH:14][C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1
Reactant: C/C(=C\c1ccc(Cl)cc1)[N+](=O)[O-]
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]cc(C)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
2.6 mmol TBD/g polystyrene (21.4 g, 55.7 mmol) was added to a suspension of (E)-1-chloro-4-(2-nitroprop-1-enyl)benzene (10 g, 50.6 mmol) and ethyl 2-isocyanoacetate (6.01 g, 53.1 mmol) in i-PrOH (40 mL) and dry THF (40 mL). The reaction mixture was stirred at room temperature overnight. The suspension was filtered, washed with i-PrOH/THF (1/1, v/v, 40 mL). The combined filtrate was evaporated under reduced pressure to furnish 11.0 g (82%) of the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]#[N:41]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:17]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:19]=[C:20]([O:22][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]#[N:41])[CH:21]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Reactant: N#CCCCCCBr
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCCCCCC#N)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 111.9 %

Procedure:
Using 0.85 g (1.88 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic acid tert-butyl ester and 6-bromo-hexanenitrile (0.33 g, 1.88 mmol) and following the procedure of Example 42(b) afforded 1.15 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (3H, m), 1.4 (9H, s), 1.6 (4H, m), 1.8 (6H, m), 3.2 (1H, m), 3.7 (1H, m), 4.05 (2H, m), 6.75 (1H, d), 6.90 (1H, s), 7.14 (3H, m), 7.34 (1H, s), 7.88 (2H, d), 8.28 (1H, d).