Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[C:8]([CH3:10])([CH3:9])[C@H:5]([CH2:6][CH2:7]1)[CH:4]([C:11](Cl)=[O:12])[C:3]2=O.C(N(CC)CC)C.C(OC([N:29]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl>[CH2:41]([N:29]1[C:3]2[C@@:2]3([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]([CH2:6][CH2:7]3)[C:4]=2[C:11](=[O:12])[N:30]1[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)Nc1ccc2ccccc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc3ccccc3c2)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 15.8 %

Procedure:
A solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 240 mg, 1.12 mmol) in 1,2-dichloroethane (8 mL) was added to a cooled (0° C.) solution of triethylamine (210 μL, 1.5 mmol) and N-benzyl-N′-naphthalen-2-yl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 37; 285 mg, 0.82 mmol) in 1,2-dichloroethane (4 mL) over 1 min. The reaction mixture was stirred at room temperature for 75 min. A solution of HCl in dioxane (4 M; 4 mL, 16 mmol) was added and the reaction mixture was heated at reflux for 1 h, allowed to cool, and concentrated. The residue was purified using an ISCO 40 g column, eluting with 50-100% ethyl acetate/hexanes. Fractions containing the product were evaporated and purified again using an ISCO 40 g column, eluting with 60-100% ethyl acetate/hexanes. Fractions containing the product were evaporated, then co-evaporated with methanol and then with diethyl ether and dried under high vacuum at room temperature overnight to give (4S,7R)-1-benzyl-7,8,8-trimethyl-2-naphthalen-2-yl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (53 mg, 16%) as a white foam. ES(+)-MS (M+H) 409.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[NH2:48][C:49]1[CH:54]=[CH:53][C:52]([S:55][C:56]2[CH:61]=[CH:60][C:59]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[CH:58][CH:57]=2)=[C:51]([NH:70][C:71]2[C:72]3[CH:80]=[CH:79][C:78]([CH:81]([CH3:83])[CH3:82])=[N:77][C:73]=3[N:74]=[CH:75][N:76]=2)[CH:50]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:48][C:49]3[CH:54]=[CH:53][C:52]([S:55][C:56]4[CH:61]=[CH:60][C:59]([NH:62][C:63]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:69])=[CH:58][CH:57]=4)=[C:51]([NH:70][C:71]4[C:72]5[CH:80]=[CH:79][C:78]([CH:81]([CH3:83])[CH3:82])=[N:77][C:73]=5[N:74]=[CH:75][N:76]=4)[CH:50]=3)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: CC(C)c1ccc2c(Nc3cc(N)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccc2c(Nc3cc(NC(=O)c4ccc(Sc5ccc(NC(=O)OC(C)(C)C)cc5)c(Nc5ncnc6nc(C(C)C)ccc56)c4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1

Procedure:
To a solution of the product from Example 1E (50 mg, 0.094 mmol) in DMSO (0.5 mL) at room temperature were added Hunig's base (49.3 μl, 0.282 mmol), the product from Example 2A (47.3 mg, 0.094 mmol), and HATU (42.9 mg, 0.113 mmol) and the reaction was stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed with water. The organic was dried over MgSO4, filtered and concentrated. The crude product was used without further purification.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH2:11][C:12]1[CH2:13][S:14](=[O:46])[C@@H:15]2[CH:35]([NH:36][C:37](=[O:44])[CH2:38][C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)[C:34](=[O:45])[N:16]2[C:17]=1[C:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].O>C(Cl)Cl>[F:7][CH2:11][C:12]1[CH2:13][S:14](=[O:46])[C@@H:15]2[CH:35]([NH:36][C:37](=[O:44])[CH2:38][C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)[C:34](=[O:45])[N:16]2[C:17]=1[C:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS(=O)[C@H]12
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CF)CS(=O)[C@H]12
Reaction time: 0.5 h
Yield: 5.9 %

Procedure:
To a solution of 0.483 g (3.0 mmoles) of diethylaminosulfur trifluoride in 10 ml of CH2Cl2 at -78° under N2 was added a solution of 1.61 g (3.0 mmoles) of benzhydryl 3-hydroxymethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate-1-oxide in 50 ml of CH2Cl2 and the mixture was stirred at -78° for 0.5 hrs, then poured into 100 ml of water. The CH2Cl2 layer was dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel with 9:1 CH2Cl2 -acetone to yield 0.095 g of benzhydryl 3-fluoromethyl-7-(2-thienyl-acetamido)-3-cephem-4-carboxylate-1-oxide in fractions 12-15, rf = 0.60 on tlc with 9:1 CH2Cl2 -acetone; ir (CHCl3) 3450 (amide N-H), 1805 (β-lactam C=O), 1725 (ester C=O), 1680 (amide C=O), 1495 ("amide II" band), and 700 (aromatic) cm-1 ; mp 205.5°-207.5° d.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:19])[O:16][C:15](=[O:17])[CH2:14][C:13](=[O:18])[O:12]1>[Br-].C[N+](C)(C)CCCCCCCCCCCCCCCC>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:14]2[C:15](=[O:17])[O:16][C:11]([CH3:19])([CH3:10])[O:12][C:13]2=[O:18])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Product: CC1(C)OC(=O)C(=Cc2ccc(Br)cc2)C(=O)O1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
A mixture of N,N,N-trimethylhexadecan-1-aminium bromide (15.76 g), 4-bromobenzaldehyde (80 g) and 2,2-dimethyl-1,3-dioxane-4,6-dione (68.6 g) was heated and stirred at 60° C. for 1 h, during which time a solid precipitated from solution. The mixture was allowed to cool to room temperature. The solid was collected by filtration and washed with cold water (600 mL). dried in vacuo at 50° C. to give 5-(4-bromobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (108 g) as a colourless solid.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:19])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:19]
Reactant: CC=CCC1Cc2ccc(OC)cc2C1=O
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 8 h
Yield: 50.9 %

Procedure:
Ozone (3 g ozone/hour) was conducted for 60 minutes while stirring through a solution, cooled to -70°, of 13.6 g of (RS)-2-(2-buten-1-yl)-6-methoxy-1-indanone in 200 ml of anhydrous dichloromethane and 400 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen and then 6.4 ml of dimethyl sulfide were added to the cold solution. The solution came to room temperature overnight and was evaporated in a vacuum. The residue was dissolved in 1600 ml of dichloromethane. The solution was treated with 600 g of silica gel and 100 ml of 10% oxalic acid solution and stirred overnight. Then, the mixture was filtered and the filtrate was concentrated in a vacuum. 6.5 g (51%) of (RS)-2-(2-oxoethyl)-6-methoxy-1-indanone were obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[CH:4][N:3]=1.[O:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([NH:25][NH2:26])=[O:24])(=[O:19])=[O:18])[CH2:13][CH2:12]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:26]/[NH:25][C:23](=[O:24])[C:22]2[CH:27]=[CH:28][CH:29]=[C:20]([S:17]([N:14]3[CH2:15][CH2:16][O:11][CH2:12][CH2:13]3)(=[O:18])=[O:19])[CH:21]=2)/[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: CC(=O)c1ccnc(Cl)c1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1ccnc(Cl)c1
Temperature: 120 °C
Yield: 60 %

Procedure:
1-(2-Chloropyridin-4-yl)ethanone (20 mg, 0.129 mmol) and 3-(morpholinosulfonyl)benzohydrazide (36.7 mg, 0.129 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography affording the title compound in a 60% yield. 1H NMR (400 MHz, CDCl3): δ 9.43 (m, 1H), 8.39 (m, 2H), 8.15 (d, 1H, J=8.0 Hz), 7.93 (d, 1H, J=7.6 Hz), 7.70 (t, 1H, J=7.6 Hz), 7.52 (m, 1H), 3.73 (m, 4H), 3.02 (m, 4H), 2.35 (s, 3H). ESI-MS: 423.1 [M+H]+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]1[C:14]2[C:13]3C=C[CH:17]=[CH:18][C:12]=3[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C(I)C.Cl>C1COCC1>[CH2:3]([C:2]1[C:1]2[S:11][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:14]=3[C:13]=2[CH:12]=[CH:18][CH:17]=1)[CH3:4]
Reactant: c1ccc2c(c1)sc1ccccc12
Reactant: [Li]CCCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cccc2c1sc1ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
n-Butyllithium (108 mmols, 46 ml of 2.4M solution in hexane) was added to a stirred solution of dibenzothiophene (10 g, 54 mmole) in dried THF (150 ml) at 0° C. over a period of 1 hr under dry N2 atmosphere. This reaction mixture was stirred 5 hrs at room temperature then the reaction mixture was cooled to −70° C. and a solution of ethyl iodide in dry THF was added dropwise and stirred at room temperature for over night. This reaction mixture was poured slowly into a cold 1N HCl (200 ml). Organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×500 ml). Organic layers mixed together and concentrated to dryness to get crude product. The crude product was purified by silica gel column chromatography.
Reaction SMILES: [OH:1][C:2]1[CH2:6][CH2:5][C:4](=[O:7])[CH:3]=1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH2:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29])=[CH:17]1>>[OH:7][C:4]1[CH2:5][CH2:6][C:2](=[O:1])[C:3]=1[CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:17]1[NH:16][C:24]2[C:19]([C:18]=1[CH2:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29])=[CH:20][CH:21]=[CH:22][CH:23]=2
Reactant: O=Cc1ccccc1
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Reactant: O=C1C=C(O)CC1
Product: CC(=O)NCCc1c(C(C2=C(O)CCC2=O)c2ccccc2)[nH]c2ccccc12

Procedure:
Using general procedure C, 3-hydroxy-cyclopent-2-enone (Lit. 16) was reacted with benzaldehyde and N-[2-(1H-indol-3-yl)-ethyl]-acetamide to give the title compound as a pink solid. MS: 387.4 ([M−H]−).
Reaction SMILES: [ClH:1].Cl.Cl.[CH:4]1([NH:7][C:8]([C:10]2[C:18]3[CH:17]=[C:16]([C:19]4[C:24]([Cl:25])=[CH:23][N:22]=[C:21](NCCCN5CCNCC5)[N:20]=4)[S:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5]1.C1(NC(C2C3C=C(C4C([Cl:57])=CN=C(Cl)N=4)SC=3C=CC=2)=O)CC1.C(OC([N:66]1[CH2:73][CH:72]2[CH:68]([CH2:69][N:70]([CH2:74][CH2:75][NH2:76])[CH2:71]2)[CH2:67]1)=O)(C)(C)C>>[ClH:25].[ClH:57].[ClH:1].[CH:4]1([NH:7][C:8]([C:10]2[C:18]3[CH:17]=[C:16]([C:19]4[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([NH:76][CH2:75][CH2:74][N:70]5[CH2:71][CH:72]6[CH:68]([CH2:67][NH:66][CH2:73]6)[CH2:69]5)[N:20]=4)[S:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5]1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: CC(C)(C)OC(=O)N1CC2CN(CCN)CC2C1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCN4CCNCC4)ncc3Cl)cc12
Agent: Cl
Product: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCN4CC5CNCC5C4)ncc3Cl)cc12

Procedure:
Using the synthetic method of 2-[5-chloro-2-(3-piperazin-1-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide tri-hydrochloride, the title compound is synthesized from 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and 5-(2-aminoethyl)-hexahydropyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester and isolated as a yellow solid. ES+(m/z) 483 (35Cl) and 485 (37Cl) [M+H].
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.[C:8](=[O:10])=[O:9].[C:11]([OH:18])(=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15].[C:19]1(=O)[O:24][C:22](=[O:23])[CH2:21][CH2:20]1>>[C:14]([OH:16])(=[O:15])[CH2:13][CH2:12][CH2:3][CH2:2][C:1]([OH:7])=[O:6].[C:22]([OH:24])(=[O:23])[CH2:21][CH2:20][CH2:19][C:8]([OH:10])=[O:9].[C:11]([OH:18])(=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CC(=O)O
Reactant: O=C1CCC(=O)O1
Reactant: O=C=O
Agent: O=C(O)CCC(=O)O
Product: O=C(O)CCCC(=O)O
Product: O=C(O)CCCCC(=O)O

Procedure:
Elsewhere, that treatise notes that malonic acid loses carbon dioxide on heating above its melting point, and in aqueous solution, undergoes decarboxylation at 70° C. (vol. 14: 794-795); that succinic acid sublimes when heated below its 188° C. melting point, dehydrates at its melting point, and forms a cyclic anhydride, succinic anhydride having mp 119.6° C. (vol. 21: 848-849); and that adipic acid, unlike glutaric acid and succinic acid, does not readily form a cyclic anhydride, but decomposes to cyclopentanone above 225° C. (vol. 1: 510-513).
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@H:13]([OH:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[NH:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]1=[S:32].[OH-].[Na+].O>O1CCCC1.CCOCC>[OH:24][C@@H:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[C:19](=[O:23])[CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:25])[CH2:2][S:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)[CH2:12]1
Reactant: S=c1cccc[nH]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CSc4ccccn4)[C@@]3(C)CC(=O)[C@@H]12
Reaction time: 0.05 h
Yield: 22.4 %

Procedure:
A solution of 21-bromo-3α-hydroxy-5α-pregnane-11,20-dione (1.0 g.) in tetrahydrofuran (10 ml) was added to a solution of pyrid-2-thione (0.5 g) in 2N-aqueous sodium hydroxide (10 ml). After allowing the mixture to stand at room temperature for 3 mins., water and ether were added. The organic layer was washed with water, dried (Na2SO4) and evaporated. The residue was subjected to preparative t.l.c. and recrystallisation from methyl acetate/petrol to give title compound (240 mg.) as white needles m.p. 184° [α]D + 130° (c 0.9).
Reaction SMILES: ClN1C(=O)CCC1=O.[CH2:9]([O:11][C:12]([C:14]1[N:15]([CH3:32])[C:16]([CH2:30][CH3:31])=[C:17]([C:28]#[N:29])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:27])=O)=[CH:21][CH:20]=1)=[O:13])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C(Cl)Cl.O>[CH2:9]([O:11][C:12]([C:14]1[N:15]([CH3:32])[C:16]([CH2:30][CH3:31])=[C:17]([C:28]#[N:29])[C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([C:25](=[O:27])[NH:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:23][CH:24]=1)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1c(-c2ccc(C(=O)O)cc2)c(C#N)c(CC)n1C
Reactant: Nc1ccccc1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(C(=O)Nc3ccccc3)cc2)c(C#N)c(CC)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add N-chlorosuccinimide (0.13 g, 1.0 mmol) to 3-(4-carboxy-phenyl)-4-cyano-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.33 g, 11.0 mmol, prepared in example E-157) and triphenyl-phosphine (0.26 g, 1.0 mmol) in methylene chloride at 0° C. with stirring. Allow the reaction to warm to room temperature. After 30 minutes, add aniline (0.18 mL, 2.0 mmol). After 2-3 hours, pour the reaction mixture into water and extract with methylene chloride. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to provide the title compound. Mass spectrum (m/e): 402.0 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[C:10]([NH:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:9]=2)[CH2:4][CH2:3]1>C(OCC)(=O)C.ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[C:10]([NH:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(CO)c(NC3CCOCC3)c2)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN1CCN(c2ccc(C=O)c(NC3CCOCC3)c2)CC1
Reaction time: 5 h
Yield: 50.3 %

Procedure:
85 mg (0.982 mmol) of manganese dioxide is added at room temperature to a solution of (4-(4-methylpiperazine-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)phenyl)methanol (100 mg, 0.327 mmol) in a mixture of ethyl acetate (10 ml) and dichloromethane (9 ml). The reaction mixture is placed in an ultrasonic bath for 5 hours. The reaction mixture is filtered, the solvents are evaporated and the crude product is purified by chromatography to yield 50.0 mg (yield=50.3%) of (4-(4-methylpiperazine-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzaldehyde in the form of a white solid. LCMS (EI, m/z): (M+1) 304.19.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](F)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.[H-].[Na+]>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)([O-:3])=[O:2]
Reactant: CN1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)CC1
Reaction time: 1 h

Procedure:
3,4-Dinitrofluorobenzene (1.86 g, 10 mmol) and 4-hydroxy-1-methylpiperidine (1.38 g, 12 mmol) were dissolved in THF (20 ml) and stirred at ambient temperature while sodium hydride (60% dispersion in mineral oil, 0.40 g, 10 mmol) was added in several small portions. The reaction mixture was stirred for one hour and then reduced in vacuo, partitioned between ethyl acetate and water, and the organic phase washed with brine, dried (MgSO4) and reduced in vacuo. The resulting residue was subject to column chromatography, eluting with 5% MeOH/DCM to give a yellow solid (1.76 g, 2:1 ratio of desired 4-(3,4-dinitro-phenoxy)-1-methyl-piperidine and a side product, 4-(4-fluoro-2-nitro-phenoxy)-1-methyl-piperidine).
Reaction SMILES: [CH3:1][CH:2]([OH:8])[CH2:3][CH2:4][C:5]#[C:6][CH3:7].[CH:9](=[O:11])[CH3:10].C[Si]([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=O)=[O:18])(C)C.C([O-])(O)=O.[Na+]>ClCCl.C(OCC)C>[F:21][C:20]([F:23])([F:22])[S:17]([O:8]/[C:2](=[C:3]1/[C@H:9]([CH3:10])[O:11][C@H:6]([CH3:7])[CH2:5][CH2:4]/1)/[CH3:1])(=[O:18])=[O:16]
Reactant: CC=O
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC#CCCC(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: C/C(OS(=O)(=O)C(F)(F)F)=C1/CC[C@@H](C)O[C@H]1C
Reaction time: 1 h
Yield: 72 %

Procedure:
In dichloromethane (3.0 mL) were dissolved hept-5-yn-2-ol (0.28 mmol) and acetaldehyde (0.34 mmol) and the solution was cooled to −78° C. before the addition of trimethylsilyltriflate (TMSOTf) (0.86 mmol) thereto. At the same temperature, the reaction solution was stirred for 1 hour, followed by slow temperature elevation to room temperature over 3 hours. Stirring was further conducted at room temperature for an additional one to two hours in the reaction solution. After the addition of an aqueous NaHCO3 solution, the reaction solution was diluted with diethylether. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. The purification of the concentrate through column chromatography afforded the title compound (Yield 72%).
Reaction SMILES: [S:1]1[C:5]([NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH3:10])=[CH:4][N:3]=[N:2]1.[H-].[Na+].[H][H].[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O1CCCC1.O>[C:7]([N:6]([C:5]1[S:1][N:2]=[N:3][CH:4]=1)[C:23]([NH:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:24])(=[O:11])[CH2:8][CH2:9][CH3:10]
Reactant: O=C=Nc1ccccc1
Reactant: [H][H]
Reactant: CCCC(=O)Nc1cnns1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC(=O)N(C(=O)Nc1ccccc1)c1cnns1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
13.2 g (0.077 mole) butyric acid-N-(1,2,3-thiadiazole-5-yl)-amide were dissolved in 150 ml absolute tetrahydrofuran and reacted with 3.36 g (0.077 mole) of a 55% dispersion of sodium hydride in oil, whereby during the addition the reaction solution through cooling is maintained at 30° C. After about 30 minutes of stirring at room temperature, the evolution of hydrogen is completed. 8.3 ml (0.077 mole) phenylisocyanate is added dropwise within about 5 minutes during which time the reaction temperature increases to 36° C. The reaction mixture is then stirred at room temperature for 1.5 hours whereby a thick crystaline slurry is formed. The reaction mixture is then introduced into a solution of 12.3 ml (0.154 mole) concentrated hydrochloric acid in 300 ml of water. Thereafter the reaction mixture is extracted with 250 ml acetic ester, the organic phase washed with water, dried over magnesium sulfate, filtered and concentrated in vacuum. There were thusly obtained colorless crystals which were digested with 50 ml diisopropylether.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:27]=[CH:26][C:3]=1[NH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH2:6]1.[CH:34](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:33][S:30]([C:28]1[CH:27]=[CH:26][C:3]2[N:4]([CH:5]3[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][CH:13]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:9][CH2:10]3)[CH:34]=[N:1][C:2]=2[CH:29]=1)(=[O:32])=[O:31]
Reactant: COC(OC)OC
Reactant: CS(=O)(=O)c1ccc(NC2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CS(=O)(=O)c1ccc2c(c1)ncn2C1CCN(CCC(c2ccccc2)c2ccccc2)CC1

Procedure:
A solution of 2-amino-4-methanesulphonyl-1-N-[-1-(3,3-diphenylpropyl)-piperidin-4-yl]aniline (prepared as described below) (50 mg, 0.1 mmol), trimethyl orthoformate (0.7 ml) and para-toluenesulphonic acid monohydrate (2 mg, 0.11 mmol) was stirred at 100° C. After 2.5 h the mixture was cooled and water (10 ml) was added. The solution was partitioned with EtOAc (2×40 ml) then the organics were combined, dried (MgSO4) and concentrated to give the title compound as an oil (47 mg, 0.1 mmol); MS: 474.