Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.N[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]([C:29]4[CH:33]=[CH:32][O:31][N:30]=4)C(OCC(Cl)(Cl)Cl)=O)[O:16][C:15]3=[O:34])=[CH:10][C:9]=2[F:35])[CH2:4]1.CC1(C)[O:41][C@H:40]([C:42](Cl)=[O:43])[CH2:39][O:38]1>N1C=CC=CC=1.ClCCl.C(OCC)(=O)C.O>[OH:41][C@@H:40]([CH2:42][OH:43])[C:39]([C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:29]4[CH:33]=[CH:32][O:31][N:30]=4)[O:16][C:15]3=[O:34])=[CH:10][C:9]=2[F:35])[CH2:4]1)=[O:38]
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Reactant: N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C([C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1)[C@@H](O)CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 143.5 %

Procedure:
3-(4-(3(S)-Aminopyrrolidin-1-yl)-3-fluorophenyl)-5(R)-(N-(2,2,2-trichloroethyl-oxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride salt (400 mg, 0.698 mM) in pyridine (5 ml) was treated dropwise with a solution of 2,2-dimethyl-1,3-dioxolan-4(S)-ylcarbonyl chloride (200 mg, 1.2 mM) in dichloromethane (2 ml), and the mixture stirred 3 hours at ambient temperature. The mixture was diluted with ethyl acetate (15 ml) and water (15 ml), the organic layer separated, washed with aqueous sodium bicarbonate (10 ml) and brine (10 ml), and evaporated, then azeotroped with toluene (20 ml). The residue was purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 100% ethyl acetate in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (435 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:9]([C:11]3[C:15]4=[N:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=[C:14]4[N:13]([CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:12]=3)=[CH:10][C:3]=12.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[C:15]4=[N:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=[C:14]4[N:13]([CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[CH:12]=3)=[CH:10][C:3]=12
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCN1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3[nH]1)cn2CCN1CCOCC1
Yield: 64.2 %

Procedure:
Treat bisazaindole 33 (40 mg, 0.067 mmol) with KOH at 3%/MeOH (10 mL) and reflux for 16 h. Concentrate the reaction medium under vacuum and divide the residue between EtOAc and saturated NaHCO3. The organic phase is washed with saturated NaHCO3, dried (Na2SO4) and submitted to flash chromatography on SiO2 (MeOH at 2-4%/CH2Cl2) to give 34 (19.0 mg, 64.2%) as a white solid: 1H NMR (CDCl3) δ 10.94 (s broad, 1H), 8.07 (d, 1H, J=5.0 Hz), 7.62 (s, 1H), 7.14 (s, 1H), 7.05 (d, 1H, J=5.3 Hz), 6.66 (d, 1H, J=1.9 Hz), 4.23 (s overlapping t, 5H, J=6.4 Hz), 3.97 (s, 3H), 3.70 (t, 4H, J=4.6 Hz), 2.79 (t, 2H, J=6.4 Hz), 2.50 (t, 4H, J=4.6 Hz), TLC (MeOH at 4%/CH2Cl2, 0.25% of NH3) Rf=0.25, m/z obs.=442.1 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26](O)=[O:27])=[CH:9]2.[CH2:29]([S:36][CH:37]([CH:40]([O:43][CH3:44])[O:41][CH3:42])[CH2:38][NH2:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O.CN(C)C=O>[CH2:29]([S:36][CH:37]([CH:40]([O:41][CH3:42])[O:43][CH3:44])[CH2:38][NH:39][C:26]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=2[N:15]([CH3:25])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)(=[O:18])=[O:17])=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Reactant: COC(OC)C(CN)SCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(SCc3ccccc3)C(OC)OC)cc2c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 80.2 %

Procedure:
To a mixture of 5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (2.50 g), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (1.79 g), diisopropylethylamine (2.00 g) and N,N-dimethylformamide (30 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 3.19 g) at room temperature, and the mixture was stirred at room temperature for 2.5 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with aqueous citric acid solution, saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (1:1-1:4, volume ratio) to give the title compound (3.11 g, yield 80%) as a colorless amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>ClCCl>[CH3:21][O:20][N:19]([CH3:18])[C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 30 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperidin-4-carboxylic acid (5.0 g, 21.8 mmol) in dichloromethane (80 mL) were added N,O-dimethylhydroxylamine hydrochloride (2.55 g, 26.1 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (9.95 g, 26.1 mmol), N-ethyl-N-isopropylpropan-2-amine (8.46 g, 65.42 mmol) and stirred at 30° C. for 16 hours. The reaction was quenched by adding water (100 ml) and extracted with ethyl acetate (200 ml*3). The combined organic layers was washed with brine, dried over sodium sulfate and concentrated under vacuum to give tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (5.7 g, yield 97.6%). LRMS (M+H+) m/z: calcd 272.17. found 273.17.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>O.CN(C=O)C>[CH2:18]([S:25][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: SCc1ccccc1
Reactant: CCOC(=O)COc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1cc(SCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 72.9 %

Procedure:
A mixture of ethyl 2-(5-fluoro-2-nitrophenoxy)acetate (11 g), benzylmercaptan (5.2 g), triethylamine (5.08 g) and DMF (50 ml) was stirred and heated to 80° C. for 7 hours. The mixture was cooled, poured into water and acidified by the addition of dilute aqueous hydrochloric acid. The mixture was extracted with diethyl ether. The organic phase was washed with water and with brine, dried (MgSO4) and evaporated to give ethyl 2-(5-benzylthio-2-nitrophenoxy)acetate (10.6 g, 68%) as a solid.
Reaction SMILES: [ClH:1].[OH:2][CH2:3][C@@H:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]1C(OC(C)(C)C)=O>CO>[ClH:1].[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:12][CH2:13][C@H:4]1[CH2:3][OH:2]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC[C@H]1CO
Agent: Cl
Solvent: CO
Product: OC[C@@H]1CCc2ccccc2N1
Reaction time: 0.5 h

Procedure:
Hydrogen chloride in methanol (1.25 mol/l, 60 ml) was added to (S)-tert-butyl 2-(hydroxymethyl)-3,4-dihydroquinoline-1(2H)-carboxylate (3.98 g, 15.1 mmol) and the mixture was refluxed for 2 h. The solvent was removed in vacuo, the residue was taken up in ethanol (5 ml) and the mixture was cooled. Diethylether (200 ml) was added and the mixture was stirred in an ice bath for 30 min. The precipitate was filtered out with suction, washed with diethylether and dried in vacuo.
Reaction SMILES: Cl.[CH3:2][CH:3]1[O:8][CH2:7][CH2:6][NH:5][CH2:4]1.[Cl:9][C:10]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:11]=1[CH2:12][N:13]1[C:18]2[N:19]=[C:20](S(C)(=O)=O)[S:21][C:17]=2[C:16](=[O:26])[N:15]=[CH:14]1>C(N(CC)CC)C.CN(C=O)C.O>[Cl:9][C:10]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:11]=1[CH2:12][N:13]1[C:18]2[N:19]=[C:20]([N:5]3[CH2:6][CH2:7][O:8][CH:3]([CH3:2])[CH2:4]3)[S:21][C:17]=2[C:16](=[O:26])[N:15]=[CH:14]1
Reactant: CS(=O)(=O)c1nc2c(s1)c(=O)ncn2Cc1cccc(Cl)c1Cl
Reactant: CC1CNCCO1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1CN(c2nc3c(s2)c(=O)ncn3Cc2cccc(Cl)c2Cl)CCO1
Temperature: 60 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
A mixture of triethylamine (2 drops), 2-methylmorpholine hydrochloride (16 mg, 0.154 mmol) and 4-(2,3-dichlorobenzyl)-2-(methylsulfonyl)thiazolo[4,5-d]pyrimidin-7(4H)-one (20 mg, 0.051 mmol) in DMF was stirred at 60° C. for 1 h. After cooled to ambient temperature, the mixture was diluted with water (10 mL) and extracted with dichloromethane (15 mL×3). The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM:MeOH=20:1 elution) to give the desired product (8 mg, 38%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 8.49 (s, 1H), 7.63 (d, J=7.2 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.16 (s, J=6.9 Hz, 1H), 5.46 (s, 2H), 3.88 (dd, J=12.3, 2.7 Hz, 1H), 3.77 (br, 2H), 3.55-3.47 (m, 2H), 3.31-3.20 (m, 1H), 2.94-2.89 (m. 1H), 1.13 (d, J=5.7 Hz, 3H); LC-MS: 411 (MH+); IR (thin film): 2976, 2920, 2855, 2360, 1627, 1605, 1555, 1495, 1444 cm−1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[N:36]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[C:35]2=[O:50].O>CN(C)C=O.CO>[O:49]=[C:43]1[CH:42]([N:36]2[C:35](=[O:50])[C:34]3[C:38](=[CH:39][CH:40]=[C:32]([CH2:31][NH:30][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][N:8]=4)=[O:12])[CH:33]=3)[C:37]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCOc1ccc(C(=O)O)nc1
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)nc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A stirred mixture of 5-ethoxy-pyridine-2-carboxylic acid (0.50 g, 3.00 mmol) and CDI (0.54 g, 3.30 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (1.15 g, 3.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. After 2 h, the solids were isolated by filtration. The product was dissolved in MeOH (200 mL) and treated with decolorizing carbon. The carbon was removed by filtration and the filtrate was concentrated until precipitation was observed. The product was isolated by filtration, washed with MeOH (5 mL) and dried in vacuo to give 5-ethoxy-pyridine-2-carboxylic acid[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.89 g, 68% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.24 min (99.33%); mp: 185-187° C.; 1H 1H NMR (DMSO-d6) δ 1.37 (t, J=7.0 Hz, 3H, CH3), 1.95-2.16 (m, 1H, CHH), 2.40-2.70 (m, 2H, CHH, CHH), 2.78-3.01 (m, 1H, CHH), 4.19 (q, J=7.0 Hz, 2H, CH2), 4.63 (d, J=6.2 Hz, 2H, CH2), 5.14 (dd, J=5.4, 12.9 Hz, 1H, CH), 7.53 (dd, J=2.9, 8.8 Hz, 1H, Ar), 7.74-7.93 (m, 3H, Ar), 8.00 (d, J=8.7 Hz, 1H, Ar), 8.32 (d, J=2.5 Hz, 1H, Ar), 9.42 (t, J=6.4 Hz, 1H, NH), 11.11 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.40, 21.99, 30.93, 42.30, 48.99, 64.07, 121.27, 122.07, 123.39, 123.50, 129.74, 131.54, 133.54, 136.79, 142.16, 147.74, 156.99, 164.09, 167.00, 167.15, 169.80, 172.73; LCMS: MH=437; Anal Calcd for C22H20N4O6: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.19; H, 4.53; N, 12.71.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4]1.[CH:9]1([OH:16])[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:3]1([CH2:2][O:15][CH:12]2[CH2:13][CH2:14][CH:9]([OH:16])[CH2:10][CH2:11]2)[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4]1
Reactant: ClCC1CC=CCC1
Reactant: OC1CCC(O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OC1CCC(OCC2CC=CCC2)CC1
Temperature: 90 °C
Reaction time: 5 h
Yield: 61.8 %

Procedure:
To toluene (500 g) were added 4-chloromethylcyclohexene (0.1 mol), 1,4-cyclohexanediol (0.5 mol), and tetrabutylammonium bromide (0.01 mol), the mixture was raised in temperature to 90° C., and a 5 N NaOH aqueous solution (100 g) was added dropwise thereto, followed by stirring for 5 hours. A toluene solution (toluene layer) was rinsed with water, concentrated, purified by silica gel chromatography, and thereby yielded 13 g of 4-(cyclohex-3-enylmethoxy)cyclohexanol with a purity of 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[N+:5]([O-:22])=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)c1cc(Cl)ccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)OC(=O)c1cc(Cl)cc[n+]1[O-]
Yield: 69.6 %

Procedure:
A solution of 2.55 g (14 mmol) of isopropyl 4-chloropyridine-2-carboxylate (Intermediate 232) and 1.4 g (26 mmol) of m-CPBA in 30 ml CH2Cl2 was stirred at room temperature for 2 d. The mixture was quenched with aqueous NaHSO3 and CH2Cl2 was removed. The aqueous residue was basified with aqueous Na2CO3, saturated with NaCl and extracted repeatedly with EtOAc. The EtOAc was dried (MgSO4) and concentrated. The residue was taken up in ether and insoluble material was filtered off. The filtrate was concentrated and the residue was chromatographed on silica gel (100% CH2Cl2 with gradient elution to 100% EtOAc) to afford 2.1 g of product as an oil. NMR (d6-DMSO): 1.3 (d, 6H), 5.3 (septet, 1H), 7.25 (m, 1H), 7.5 (d, 1H), 8.1 (d, 1H).
Reaction SMILES: [N:1]([C:4]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O)=[N+]=[N-].O=S(Cl)[Cl:25]>>[Cl:25][C:6]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:1]=[C:4]2[C:5]=1[CH:15]=[CH:16][CH:17]=[C:18]2[C:19]([F:22])([F:21])[F:20]
Reactant: [N-]=[N+]=Nc1c(C(=O)Nc2ccccc2)cccc1C(F)(F)F
Reactant: O=S(Cl)Cl
Product: FC(F)(F)c1cccc2c(Cl)n(-c3ccccc3)nc12

Procedure:
2-Azido-N-phenyl-3-trifluoromethyl-benzamide (310 mg, 1 mmol, compound of formula (X)) was heated in 2 ml of SOCl2 in a sealed vial at 100° C. for 4 hours. After evaporation of SOCl2 in vacuo the residue was purified by column chromatography on silica (n-heptane/ethyl acetate, 50:50, as eluent). Yield: 212 mg (72%).
Reaction SMILES: [NH:1]1[C:10](=O)C2NC=NC=2N[C:2]1=O.O=P(Cl)(Cl)Cl.[Cl:17][C:18]1[N:26]=[C:25]2[C:21]([N:22]=[CH:23][NH:24]2)=[C:20](Cl)[N:19]=1.CNC>>[Cl:17][C:18]1[N:26]=[C:25]2[C:21]([N:22]=[CH:23][NH:24]2)=[C:20]([N:1]([CH3:10])[CH3:2])[N:19]=1
Reactant: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Agent: CNC
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)c1nc(Cl)nc2[nH]cnc12

Procedure:
Xanthine (2,6-dihydroxy-9H-purine) is converted by reaction with phosphorus oxytrichloride in accordance with G. B. Elion and G. H. Hitchings, J. Am. Chem. Soc. 78, 3508 (1956) into the 2,6-dichloro-9H-purine and the latter is reacted with N,N-dimethylamine in accordance with J. A. Montgomery and L. B. Holum, J. Am. Chem. Soc. 80, 404 (1958) to form 2-chloro-6-(N,N-dimethylamino)-9H-purine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:28][CH3:29])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)[CH2:28][CH3:29])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
A mixture of 4-fluoro-N2-phenylbenzene-1,2-diamine (199 mg, 0.98 mmol), (S)-2-tertbutoxycarbonylaminobutyric acid (219 mg, 1.08 mmol), HOAt (147 mg, 1.08 mmol), 4-methylmorpholine (0.238 mL, 2.16 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (207 mg, 1.08 mmol) in DCM (5 mL) was stirred at RT for 2 h. The reaction mixture was partitioned between DCM (50 mL) and a saturated solution of NaHCO3. The organic layer was dried (Na2SO4), concentrated in vacuo and the resulting residue dissolved in AcOH (10 mL) and stirred for 18 h at 70° C. After cooling to RT, the volatiles were evaporated under reduced pressure and the residue was partitioned between DCM (50 mL) and a saturated aqueous solution of NaHCO3. The organic layer was washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) to afford the title compound as a beige solid (234 mg, 64%). LCMS (Method C): RT 3.82 min [M+H]+ 370.5.
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([CH:44]=2)[C:42]#[N:43])O1>>[C:42]([C:41]1[CH:44]=[C:37]([C:2]2[C:3]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=3)=[O:8])[CH:22]=2)[CH:38]=[N:39][CH:40]=1)#[N:43]
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: N#Cc1cncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)c(F)c3)cnc2N2CC[C@@H](O)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 198.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a yellow solid. UPLC-MS (Condition 3) tR=1.05 min, m/z=488.3 [M+H]+, m/z=486.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.75 (s, 1H) 1.81-1.92 (m, 1H) 2.87 (d, J=11.25 Hz, 1H) 3.15-3.27 (m, 2H) 3.33-3.44 (m, 1H) 4.21 (br. s, 1H) 4.87 (d, J=3.42 Hz, 1H) 7.51-7.64 (m, 2H) 7.98 (dd, J=13.20, 2.20 Hz, 1H) 8.08 (d, J=2.20 Hz, 1H) 8.40 (t, J=1.96 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.90 (d, J=1.96 Hz, 1H) 9.03 (d, J=1.96 Hz, 1H) 10.31 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]([C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:13]O)[CH2:9][N+:8]([O-:21])=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:6]=2[CH:29]=1.[CH:30](=O)[CH3:31].N>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:30]([CH3:31])=[N:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[C:10]3[CH2:9][N+:8]([O-:21])=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:6]=2[CH:29]=1
Reactant: CC=O
Reactant: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2NC(C(=NO)N2CCOCC2)C1
Agent: N
Solvent: CC(=O)O
Product: Cc1nc(N2CCOCC2)c2n1-c1ccc(Cl)cc1C(c1ccccc1F)=[N+]([O-])C2

Procedure:
A mixture of 4.2 g (0.01 mole) of 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-N-hydroxy-α-(4-morpholinyl)-1H-1,4-benzodiazepine-2-methanimine 4-oxide, 50 ml of glacial acetic acid and 4 ml of acetaldehyde was heated to reflux for 5 minutes. The cooled reaction mixture was poured on ice, made alkaline with ammonia and extracted with methylene chloride. The extracts were dried and evaporated and the residue was crystallized from ether/2-propanol to yield yellow crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[CH:18][C:17]([CH2:20][C:21]([NH2:23])=[O:22])=[C:16]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-])=O)[CH:27]=4)[CH:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[H][H]>C(O)(=O)C.[C].[Pd]>[NH2:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][NH:24][C:16]1[CH:15]=[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:12][CH:11]=2)[N:19]=[CH:18][C:17]=1[CH2:20][C:21]([NH2:23])=[O:22]
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NCc1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: NC(=O)Cc1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NCc1cccc(N)c1
Yield: 99.3 %

Procedure:
21 mg of 6-[(4-morpholinophenyl)amino]-4-[(3-nitrobenzyl)amino]pyridine-3-carboxyamide (the compound of Example 102) was dissolved in 1 mL of acetic acid, to which 21 mg of 10% palladium carbon was added, and stirred in a hydrogen atmosphere at room temperature for 4 hours. The 10% palladium carbon was filtered off, and the solvent was evaporated to obtain 19.5 mg (100%) of the title compound as a light gray solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH2:11])[CH2:8]2.[CH2:12]1[CH2:19][O:18][S:15](=[O:17])(=[O:16])[CH2:14][CH2:13]1>O1CCOCC1>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][CH2:19][CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:17])=[O:16])[CH2:8]2
Reactant: O=S1(=O)CCCCO1
Reactant: NC1C2CC3CC(C2)CC1C3
Solvent: C1COCCO1
Product: O=S(=O)(O)CCCCNC1C2CC3CC(C2)CC1C3
Temperature: 25 °C

Procedure:
To a solution of 2-adamantanamine (1.06 g, 7.0 mmol) in 1,4-dioxane (6 mL) was added 1,4-butane sultone (955 mg, 6.7 mmol). The solution was stirred at reflux for 5 hours. The reaction was cooled to room temperature. The solid was collected by filtration. It was suspended in EtOH (25 mL) and the mixture was heated to reflux for 1 minute before the solid was filtered. It was washed with EtOH (1×15 mL) and dried in vacuo. Yield: 55%. 1H NMR (D2O, 500 MHz) δ ppm 3.29 (m, 1H), 2.97 (m, 2H), 2.83 (m, 2H), 2.02 (m, 2H), 1.83 (m, 2H), 1.68 (m, 14H). 13C NMR (D2O, 125 MHz) δ ppm 63.07, 50.25, 45.03, 36.55, 36.31, 29.85, 29.05, 26.68, 26.41, 24.47, 21.61. ES-MS 286 (M−1).
Reaction SMILES: [CH:1]1([NH:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>O1CCCC1.O.C(OCC)(=O)C>[Br:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:6]([CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: C1CCC(NC2CCCC2)CC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Br)cc1)N(C1CCCCC1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (+5° C.) stirred solution of N-cyclopentyl-N-cyclohexyl amine (4.0 g, 24 mmol) and triethylamine (2.5 g, 24 mmol) in tetrahydrofuran (50 ml) was added dropwise a solution of 4-bromobenzoyl chloride (5.0 g, 23 mmol) in tetrahydrofuran (20 ml). The reaction was stirred at room temperature overnight and worked up by diluting with water and ethyl acetate. The layers were separated and the organic layer was washed twice with 0.5N KHSO4, twice with 5% NaHCO3, and once with saturated aqueous NaCl solution. After drying over MgSO4, the drying agent was filtered, the filtrate concentrated in vacuo, and the residue recrystallized from cyclohexane to give the title compound: m. p. 110-112° C.