Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH3:35])[CH:29]=4)[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:41].[NH:42]1[CH2:47][CH2:46][CH:45]([NH:48]C(=O)OC(C)(C)C)[CH2:44][CH2:43]1>>[NH2:48][CH:45]1[CH2:46][CH2:47][N:42]([C:16]2[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH3:35])[CH:29]=4)[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]3[CH:12]=[CH:11][C:10](=[O:41])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=2)[CH2:43][CH2:44]1
Reactant: Cc1cc(C(=O)Nc2ccc(C)c(-c3nc(S(C)(=O)=O)nc4c3ccc(=O)n4-c3c(F)cccc3F)c2)ccc1F
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: Cc1cc(C(=O)Nc2ccc(C)c(-c3nc(N4CCC(N)CC4)nc4c3ccc(=O)n4-c3c(F)cccc3F)c2)ccc1F

Procedure:
The title compound was prepared as described in Example 2 from N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-4-fluoro-3-methylbenzamide and 1,1-dimethylethyl 4-piperidinylcarbamate: LC-MS m/z 599 (M+H)+, 1.99 min (ret time).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][CH3:13])[C:5]#[N:6].Cl.[Cl:15][CH2:16][C:17](=N)OCC>C(O)C>[ClH:15].[CH2:11]([N:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=[C:17]1[CH2:16][Cl:15])[CH2:12][CH3:13]
Reactant: CCOC(=N)CCl
Reactant: CCCNc1ccc(C#N)cc1N
Agent: Cl
Solvent: CCO
Product: CCCn1c(CCl)nc2cc(C#N)ccc21

Procedure:
A solution of 3-amino-4-n-propylaminobenzonitrile (7.38 g, 42.1 mmol) and ethyl chloroacetimidate hydrochloride (9.92 g, 63.2 mmol) in ethanol (100 mL) is heated at reflux for 17 h, then cooled and concentrated to give 1-n-Propyl-2-chloromethyl-5-cyanobenzimidazole hydrochloride. Prior to use in the next step, this material is converted to free base by adding aqueous bicarbonate and extracting with dichloromethane, drying (Na2SO4), and concentrating.
Reaction SMILES: [OH-].[Na+].O.[CH:4]([O:7][C:8](Cl)=[O:9])([CH3:6])[CH3:5].[CH2:11]([N:18]1[CH2:25][CH:24]2[CH2:26][CH:20]([CH2:21][NH:22][CH2:23]2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH2:11]([N:18]1[CH2:19][CH:20]2[CH2:26][CH:24]([CH2:23][N:22]([C:8]([O:7][CH:4]([CH3:6])[CH3:5])=[O:9])[CH2:21]2)[CH2:25]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(CN2CC3CNCC(C3)C2)cc1
Reactant: CC(C)OC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)OC(=O)N1CC2CC(CN(Cc3ccccc3)C2)C1
Reaction time: 3 h
Yield: 95 %

Procedure:
NaOH (6.0 mL; 10M), H2O (10 mL) and iso-propylchloroformate (55 mmol) were added to a solution of 3-benzyl-3,7-diazabicyclo[3.3.1]nonane (10.8 g; 50 mmol; see Example E above)-in DCM (50 mL) The reaction mixture was stirred for 3 h and the phases were then separated. The organic phase -was washed with H2O and brine, dried and concentrated to give the sub-title compound in a 95% yield.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6].Br[CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:1][CH2:2][CH2:3][N:4]([S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6])[CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCO
Reactant: CC(C)(C)OC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCN(CCO)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 15 h

Procedure:
To a solution of 8.7 g of N-(2-hydroxy-ethyl)-2-nitro-benzenesulfonamide (Skerlj, R. T.; Nan, S.; Zhou, Y.; Bridger, G. J. Tetrahedron Lett. 2002 (43) 7569-7571) in 87 ml of DMF, under argon, was added 8.8 ml of tert-butyl 3-bromopropionate and 14.6 g of K2CO3. The mixture was stirred for 15 hours at 40° C. and a further 5 ml of tert-butyl 3-bromopropionate were then added. The mixture was heated at 40° C. overnight and then filtered through a sinter of porosity 4. The cake was washed with ethyl acetate and the filtrate was then concentrated under reduced pressure and purified by flash chromatography on silica (Merck EasyVarioPrep 400 g column, Si60 15-40 μm), using a gradient of 0 to 10% EtOAc in DCM. The fractions containing the desired product were combined and concentrated under reduced pressure. 9.54 g of tert-butyl 3-[(2-hydroxy-ethyl)-(2-nitro-benzenesulfonyl)-amino]-propionate were obtained. LC/MS (C): tr=3.39 min; [M+Na]+: m/z 397.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C@@H:9]2[CH2:11][N:10]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1)#[N:2].[CH2:21]1[CH:25]2[CH2:26][NH:27][CH2:28][CH:24]2[CH2:23][N:22]1[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>C(O)(C)C>[C:15]([O:14][C:12]([NH:10][C@H:9]([CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:20][CH:19]=1)[CH2:11][N:27]1[CH2:26][CH:25]2[CH2:21][N:22]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:23][CH:24]2[CH2:28]1)=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1C[C@H]1COc1ccc(C#N)cc1
Reactant: O=C(OCc1ccccc1)N1CC2CNCC2C1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@H](COc1ccc(C#N)cc1)CN1CC2CN(C(=O)OCc3ccccc3)CC2C1
Temperature: 56 °C
Reaction time: 24 h
Yield: 80.2 %

Procedure:
tert-Butyl (2S)-2-[(4-cyanophenoxy)methyl]aziridine-1-carboxylate (2.5 g, 9.1 mmol; see step (f) above) and benzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2.24 g, 9.1 mmol; see step (h) above) was dissolved in isopropanol (30 mL) and was stirred at 56° C. for 24 h. The solvent was then evaporated. The product was purified by chromatography on silica (ethyl acetate, 0–5% MeOH eluant), giving 3.8 g (80%) of the sub-title compound.
Reaction SMILES: C(O[K])CCC.[C:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[NH:18][C:19]([C:21]1[N:22]=[C:23]([NH:26][CH:27]([CH3:29])[CH3:28])[S:24][CH:25]=1)=O)(=[O:9])[CH3:8].[ClH:30]>C(O)CCC>[ClH:30].[CH:27]([NH:26][C:23]1[S:24][CH:25]=[C:21]([C:19]2[CH:8]=[C:7]([OH:9])[C:10]3[C:11](=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[N:18]=2)[N:22]=1)([CH3:29])[CH3:28]
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2csc(NC(C)C)n2)c1
Agent: CCCCO[K]
Agent: Cl
Solvent: CCCCO
Product: COc1ccc2c(O)cc(-c3csc(NC(C)C)n3)nc2c1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A solution of t.BuOK (2.42 g, 21 mmol) in anhydrous t.BuOH (40 mL) was heated to reflux. Compound 70 (1.8 g, 5.4 mmol) was added portion-wise over a 5 min period, and the dark red solution formed was stirred at reflux for an additional 20 min. The mixture was cooled to rt, and HCl (4 M in dioxane, 8.0 mL, 32 mmol) was added, after which the reaction mixture was concentrated under vacuum. In order to assure that all of the HCl and dioxane were removed, the crude product was re-dissolved in CH2Cl2 twice and thoroughly evaporated to obtain the slightly impure HCl salt of compound 71 (1.62 g) as a brown solid. The product was dissolved in CH2Cl2 and washed with saturated NaHCO3, after which the aqueous phase was extracted several times with CH2Cl2. The combined organic phases were dried (MgSO4) and evaporated to give compound 71 (1.38 g, 81%) as a light brown solid (>95% pure according to HPLC tests). 1H-NMR (MeOH-d4, 400 MHz): δ 1.30 (d, J=6.0 Hz, 6H), 3.93 (s, 3H), 3.95-4.07 (m, 1H), 6.73 (s, 1H), 6.99 (dd, J=2.4, 9.2 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.37 (s, 1H), 8.10 (d, J=9.2 Hz, 1H).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1>CN(C)C=O>[N:26]([C:23]1[CH:24]=[CH:25][C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]2)=[CH:21][CH:22]=1)=[C:1]=[S:2]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N=C=S)cc2)CC1
Temperature: -15 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A mixture of thiocarbonyldiimidazole (4.46 g, 25.0 mmol) (Aldrich) and N,N-dimethylformamide (20 mL) was cooled to about −15° C. and a solution of 4-(4-methyl-1-piperazinyl)benzenamine (prepared according to the procedure of Chong, W. K. et al. WO9921845; 4.78 g, 25.00 mmol) was added over a period of 30 min. The cooling bath was removed and the mixture was stirred for 1 h. The mixture was cooled to 0° C. and ice-water was added. After 30 min, the mixture was extracted with ether (3×200 mL), dried (Na2SO4), filtered, and evaporated to give 1-(4-isothiocyanatophenyl)-4-methylpiperazine (4.84 g, 83%) as a pale purple solid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:6]([C:15]2[CH:16]=[C:17]([CH3:23])[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)=[N:7][C:8](S(C)(=O)=O)=[N:9][CH:10]=1.[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31]>>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:6]([C:15]2[CH:16]=[C:17]([CH3:23])[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)=[N:7][C:8]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[N:9][CH:10]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(C)c1=O
Product: Cc1cc(-c2nc(NS(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(C)c1=O

Procedure:
The title compound of Example 149, step 4 was treated with MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.42 (s, 1H), 8.36 (s, 1H), 8.10-8.12 (m, 2H), 6.98-7.05 (m, 2H), 6.87-6.92 (m, 1H), 3.64 (s, 3H), 3.45 (s, 3H), 2.22 (s, 3H). LCMS: 423.0 (M+1)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29]3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:37])[CH:3]=1.[CH:38]1([S:41]([NH2:44])(=[O:43])=[O:42])[CH2:40][CH2:39]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:44][S:41]([CH:38]4[CH2:40][CH2:39]4)(=[O:43])=[O:42])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:24][CH2:25][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29]3)[CH2:27][CH2:28]2)=[O:22])=[C:4]([CH3:37])[CH:3]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC3(C=Cc4ccccc43)CC2)cnc2c(C(=O)O)cnn12
Product: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC3(C=Cc4ccccc43)CC2)cnc2c(C(=O)NS(=O)(=O)C3CC3)cnn12
Yield: 58.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-2-methylphenylamino)-6-(spiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.03 g, 0.06 mmol) obtained in Example 109, step 2 and cyclopropanesulfonamide (0.037 g, 0.30 mmol), the 30 title compound (0.021 g, 58%) was obtained.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[S:14][CH:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[N:17]=3)[CH:10]=[N:9]2)=CC=1.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[NH:9]1[CH:10]=[C:11]([C:13]2[S:14][CH:15]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:17]=2)[CH:12]=[N:8]1
Reactant: COc1ccc(Cn2cc(-c3nc(Nc4ccccn4)cs3)cn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(Nc2csc(-c3cn[nH]c3)n2)nc1
Yield: 61.5 %

Procedure:
According to Scheme 1 Step 10: A solution of N-(2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-4-yl)pyridin-2-amine (0.39 mmol, 143 mg) in TFA (2 mL) was microwaved for 10 minutes at 120° C. The reaction mixture was neutralized with a solution of NaOH (1 M) and was extracted with DCM. The organic phase was dried over MgSO4, was filtered and was concentrated. The resulting crude product was purified by flash chromatography over silica gel using DCM/EtOH/NH3 (100:0:0 to 90:9:1) as eluent to yield 2-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-4-amine (0.24 mmol, 58 mg, 61%) as an orange solid.
Reaction SMILES: C([O:4][C:5]1[C:10]2[C:11]([CH3:21])=[C:12](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)C=C.C(O[C:25]([C:27]1OC2C=CC=C(OCC=C)C=2[C:31]=1C)=O)C>>[CH2:31]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:11]([CH3:21])[C:10]=2[C:5]=1[OH:4])[CH:27]=[CH2:25]
Reactant: C=CCOc1cccc2oc(/C=C/C(=O)OCC)c(C)c12
Reactant: C=CCOc1cccc2oc(C(=O)OCC)c(C)c12
Product: C=CCc1ccc2oc(/C=C/C(=O)OCC)c(C)c2c1O

Procedure:
Following the procedure of Example 134 but substituting an equivalent amount of the title compound of Example 167 for ethyl-4-allyloxy-3-methylbenzofuran-2-carboxylate, there was obtained the title compound, m.p. 125°-127° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[C:22]([F:31])[C:23]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].ClC1C=CC=C(C(OO)=[O:40])C=1.[K+].[Br-]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:16]2[NH:20][C:19]3[CH:21]=[C:22]([F:31])[C:23]([N:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:24][C:18]=3[N:17]=2)=[O:40])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:11])([F:13])[F:12]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2cc(N3CCCCC3)c(F)cc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2cc(N3CCCCC3)c(F)cc2[nH]1
Yield: 76.5 %

Procedure:
The title compound (0.18 g, 78%) was prepared by the above general procedure using 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylthio]-6-fluoro-5-(piperidin-1-yl)-1H-benzimidazole (0.23 g, 0.5 mmol) (obtained in example 16), m-chloroperbenzoic acid (50%, 0.2 g, 0.6 mmol) and chloroform (20 mL). mp 99-100° C.; IR (KBr) 3413, 1070 cm- 1; 1H NMR (DMSO-d6) δ 1.52 (m, 2H, CH2), 1.70 (m, 4H, (CH2)2), 2.20 (s, 3H, CH3) 3.98 (t,J=4.5 Hz, 4H, N(CH2)2), 4.80 (ABq,J=12.9 Hz, Δv=9.1 Hz, 2H, SOCH2), 4.94 (q,J=8.1 Hz, 2H, OCH2CF3), 7.12 (d,J=5.8 Hz, 1H), 7.18 (d,J=7.8 Hz, 1H), 7.44 (d,J=12.7 Hz, 1H), 8.32 (d,J=5.5 Hz, 1H); Mass (m/z) 454 (M -16).
Reaction SMILES: [CH:1]1[C:6]([CH2:7]O)=[CH:5][CH:4]=[N+:3]([O-])[CH:2]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]2[CH:48]([N:49]3[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]3)[C:43]3=[N:44][CH:45]=[CH:46][CH:47]=[C:42]3[CH2:41][CH2:40][C:39]=2[CH:55]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]2[CH:48]([N:49]3[CH2:50][CH2:51][N:52]([CH2:7][C:6]4[CH:5]=[CH:4][N:3]=[CH:2][CH:1]=4)[CH2:53][CH2:54]3)[C:43]3=[N:44][CH:45]=[CH:46][CH:47]=[C:42]3[CH2:41][CH2:40][C:39]=2[CH:55]=1
Reactant: [O-][n+]1ccc(CO)cc1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2N1CCNCC1
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1ccc2c(c1)CCc1cccnc1C2N1CCN(Cc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 75.5 %

Procedure:
To a mixture of 213 mg (1.70 mmol) of 4-pyridylcarbinol N-oxide and 563 mg (1.70 mmol) of carbon tetrabromide in 14 mL of dry methylene chloride at room temperature and under an argon atmosphere was added in one portion 446 mg (1.70 mmol) of triphenylphosphine. After 45 minutes, 313 mg (0.997 mmol) of (+)-8-chloro-6,11-dihydro-11-(4-piperazinyl)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine was added followed by 237 mL (1.78 mmol) of triethylamine. The reaction mixture was then allowed to stir at room temperature overnight, after which it was taken up in methylene chloride and washed once with 0.5M aqueous sodium bicarbonate and then brine. The organic portion was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via flash chromatography (5% methanol saturated with ammonia in methylene chloride) to provide 305 mg of (+)-8-chloro-6,11-dihydro-11-[4-(4-pyridinylmethyl)-1-piperazinyl]-5h-benzo[5,6]cyclohepta-[1,2-b]pyridine, N-oxide as a glass: MS (CI) m/z 421 (M+ +1);
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[OH:4].[C:26]1([C:37](O)=[O:38])[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:37]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=23)=[O:38])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)c1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)c1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol (448 mg, 1.24 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (234 mg, 1.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (357 mg, 1.86 mmol) and 1-hydroxybenzotriazole hydrate (190 mg, 1.24 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the objective substance (444 mg, 67%).
Reaction SMILES: O=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH2:3][C:4]#[N:5].C(N(CC)CC)C.Cl.[C:20]([NH:24][NH2:25])([CH3:23])([CH3:22])[CH3:21]>CCO.CCOC(C)=O>[C:20]([N:24]1[C:4]([NH2:5])=[CH:3][C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[N:25]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: N#CCC(=O)c1ccccn1
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)n1nc(-c2ccccn2)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
To a stirred solution of 3-oxo-3-pyridin-2-yl-propionitrile (0.40 g, 2.7 mmol; CAS 54123-21-6) at r.t. in EtOH (10 ml) under an argon atmosphere were added triethylamine (1.1 ml, 8.2 mmol) and t-butylhydrazine hydrochloride (1.02 g, 8.2 mmol). The mixture was heated to reflux and stirring was continued for 2 hrs. The orange solution was cooled to r.t. The solids were filtered off. The filtrate was concentrated to leave an orange viscous oil which was taken up in EtOAc and washed with water. The aqueous layer was extracted with EtOAc and with CH2Cl2/MeOH 9:1. The combined organics were dried over MgSO4, filtered and concentrated. After silica gel chromatography using CH2Cl2/MeOH as gradient, the product was obtained as off-white solid (0.366 g, 62%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH2:12][CH3:13])=[CH:4][C:3]=1F.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:22][S:23]([CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:25])=[O:24]>CS(C)=O.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH2:12][CH3:13])=[CH:4][C:3]=1[N:31]1[CH2:30][CH2:29][N:28]([CH2:27][CH2:26][S:23]([CH3:22])(=[O:24])=[O:25])[CH2:33][CH2:32]1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1cc(F)c(C)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
1-Methyl-2-fluoro-4-(ethyloxy)-5-nitrobenzene (Example 215, step A) (5.74 g, 28.8 mmol) was dissolved in DMSO (60 mL). K2CO3 (11.9 g, 86.4 mmol) and 1-[2-(methylsulfonyl)ethyl]piperazine hydrochloride (Example 148, step B) (9.85 g, 43.2 mmol) were added and the reaction mixture was heated to 100° C. and allowed to stir overnight. The mixture was cooled to rt then diluted with DCM and filtered. The filtrate was poured into H2O and extracted with DCM. The combined organics were dried with MgSO4, filtered, and concentrated in vacuo to give the title compound of Step A (9.70 g, 26.1 mmol, 90%) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 6.51 (s, 1H), 4.11 (q, J=7.0 Hz, 2H), 3.16 (t, J=6.5 Hz, 2H), 3.03 (s, 3H), 3.00-2.91 (m, 6H), 2.72-2.62 (m, 4H), 2.21 (s, 3H), 1.44 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C@:2]1([NH:19]C(=O)OC(C)(C)C)[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]2[N:12]=[C:11]([C:13](F)(F)F)[O:10][N:9]=2)[C:3]1([CH3:18])[CH3:17].N1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(C(Cl)=O)CCCCC1.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:13]1([C:11]2[O:10][N:9]=[C:8]([CH2:7][C@@H:4]3[CH2:5][CH2:6][C@:2]([CH3:1])([NH2:19])[C:3]3([CH3:17])[CH3:18])[N:12]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CC[C@@H](Cc2noc(C(F)(F)F)n2)C1(C)C
Reactant: c1ccncc1
Agent: Cl
Agent: O=C(Cl)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)[C@H](Cc2noc(C3CCCCC3)n2)CC[C@]1(C)N
Reaction time: 3 h

Procedure:
To a solution of tert-butyl {(1S,3S)-3-[(2Z)-2-amino-2-(hydroxyimino)ethyl]-1,2,2-trimethylcyclopentyl}carbamate (prepared in Step-1 example 56)(0.3 g, 1 mmol) in toluene, pyridine (0.079 g, 1 mmol) and cyclohexanecarbonylchloride was added and stirred for 3 hours. The reaction mixture was refluxed for another 12 h. The reaction mixture diluted with ethyl acetate, washed with 0.1N HCl. Ethyl acetate layer was separated, dried and concentrated, residue purified by silica column chromatography using 20% ethyl acetate in hexane. m/z (M+1)−100: 292.1. The product that obtained was dissolved in ethyl acetate. To this a solution of saturated HCl in ethyl acetate (2 mL) was added and reaction mixture was stirred at room temperature for two hours. The volatiles were removed under reduced pressure and triturated with hexane to afford the desired product. 1H NMR (400 MHz, d6-DMSO) δ ppm: 0.8 (s, 3H), 0.9 (s, 3H), 1.2 (s, 3H), 1.42-1.50 (m, 3H), 1.52-1.72 (m, 2H), 1.89-1.92 (m, 5H), 1.95-1.98 (m, 3H), 2.13-2.15 (m, 1H), 2.51-2.54 (m, 1H), 2.74 (m, 1H), 3.02 (m, 1H), 7.95 (bs, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[C:17]2[C:4]=1[C@@:5]1([CH3:29])[C@H:14]([CH2:15][S:16]2(=[O:25])=[O:24])[C@:13]2([CH3:26])[C@H:8]([C:9]([CH3:28])([CH3:27])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1.[CH3:30][N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.CN>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:20]=[C:19]([C:21]([NH:31][CH3:30])=[O:22])[CH:18]=[C:17]2[C:4]=1[C@@:5]1([CH3:29])[C@H:14]([CH2:15][S:16]2(=[O:25])=[O:24])[C@:13]2([CH3:26])[C@H:8]([C:9]([CH3:28])([CH3:27])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(OC)c2c(c1)S(=O)(=O)C[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.6 %

Procedure:
A mixture of (1R,10R,11S,16S)-3-methoxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-5-carboxylic acid (80) (0.26 g, 0.61 mmol), HATU, (0.36 g, 0.93 mmol), NMM (0.20 mL, 1.9 mmol) and methylamine (2 M in THF, 1.5 mL, 3.0 mmol) in THF (10 mL) and DMF (2.0 mL) was stirred at room temperature for 18 h in a sealed tube. The reaction mixture was concentrated under reduced pressure and the residue was quenched with water. The resulting solid was collected by filtration to give (1R,10R,11S,16S)-3-methoxy-N,1,11,15,15-pentamethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-5-carboxamide (81) (0.11 g, 41%) as a white solid. 1H NMR (CDCl3): δ 7.67 (d, 1H), 7.61 (d, 1H), 6.27 (s, 1H), 3.91 (s, 3H), 3.40-3.17 (m, 3H), 3.01 (d, 3H), 2.30 (d, 1H), 1.78-1.28 (m, 10H), 1.23-1.00 (m, 3H), 0.97 (s, 3H), 0.87 (s, 3H), 0.84 (s, 3H). MS m/z 434 (C24H35NO4S+H+).