Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=2)[C:4](=[O:5])[NH:3]1.ClC1C=C(N2C(=O)NNC2=O)C=C(Cl)C=1.CBr.[C:34](Cl)(=[O:36])[CH3:35]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][N:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=2)[C:4](=[O:5])[N:3]1[C:34](=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cn1[nH]c(=O)n(-c2cc(Cl)cc(Cl)c2)c1=O
Agent: CBr
Agent: O=c1[nH][nH]c(=O)n1-c1cc(Cl)cc(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)n1c(=O)n(-c2cc(Cl)cc(Cl)c2)c(=O)n1C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a solution of 2.6 g of 1-methyl-4-(3',5'-dichlorophenyl) urazole, which had been prepared by reacting 4-(3',5'-dichlorophenyl) urazole and methyl bromide in an equimolar proportion, and 1.0 g of triethylamine in 10 ml of N,N-dimethylformamide was added 0.8 g of acetyl chloride in small increments at room temperature with agitation. After completing the addition, the reaction was carried out on a water bath for 2 hours with continued agitation. The solvent was removed by distillation into vacuo and the mass was poured in water to precipitate crystals which were recrystallized from ethanol to obtain 2.3 g of 1-methyl-2-acetyl-4-(3',5'-dichlorophenyl) urazole in a yield of 76%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:48])([CH3:47])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:46])([C@@:13]3([CH3:45])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.[C:51]([NH:54][C:55]1([C:70]([O:72][CH3:73])=[O:71])[CH2:60][CH2:59][C:58](B2OC(C)(C)C(C)(C)O2)=[CH:57][CH2:56]1)(=[O:53])[CH3:52]>>[C:51]([NH:54][C:55]1([C:70]([O:72][CH3:73])=[O:71])[CH2:60][CH2:59][C:58]([C:7]2[C:8]([CH3:48])([CH3:47])[C@H:9]3[C@:22]([CH3:25])([CH2:23][CH:24]=2)[C@@H:21]2[C@:12]([CH3:46])([C@@:13]4([CH3:45])[C@H:18]([CH2:19][CH2:20]2)[C@H:17]2[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]2([NH:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([S:41]([CH3:44])(=[O:42])=[O:43])[CH2:37][CH2:36]2)[CH2:15][CH2:14]4)[CH2:11][CH2:10]3)=[CH:57][CH2:56]1)(=[O:53])[CH3:52]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: COC(=O)C1(NC(C)=O)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(NC(C)=O)(C(=O)OC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 58.3 %

Procedure:
The title compound was prepared following the method described in step 1 for the preparation of Example 1, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a, 5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (triflate-2) and methyl 1-acetamido-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate as the reactants. The product was obtained as a mixture of diastereomers in 58.3% yield. MS: m/e 794.6 (M+H)+, 2.718 min (method 8). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.71 (d, J=5.5 Hz, 1H), 5.28 (br. s., 1H), 5.22 (s, 1H), 4.73 (br. s., 1H), 4.60 (br. s., 1H), 3.75 (s, 3H), 3.15 (d, J=10.5 Hz, 2H), 2.92-2.79 (m, 4H), 2.73-2.53 (m, 4H), 2.52-2.22 (m, 7H), 2.20-2.08 (m, 5H), 2.03 (br. s., 1H), 2.00 (d, J=1.8 Hz, 3H), 1.98-1.75 (m, 7H), 1.70 (s, 3H), 1.68-1.20 (m, 15H), 1.14-1.04 (m, 6H), 1.00-0.91 (m, 6H), 0.86 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[CH:20]([O:19][CH:13]([CH2:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([CH2:3][CH2:2][O:1][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=2)=[O:33])[CH:5]=1)[C:14]([OH:16])=[O:15])([CH3:21])[CH3:22]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Reactant: COc1cccc(N=C=O)c1
Product: COc1cccc(NC(=O)OCCc2cc(CC(OC(C)C)C(=O)O)ccc2OC)c1

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 3-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: C1(O)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:14]([O:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28]([OH:32])=[CH:29]2)=[CH:24][C:23]=1[Br:33])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Br[CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[Na+].[I-]>CC(C)=O.CCOC(C)=O>[CH2:14]([O:21][C:22]1[C:23]([Br:33])=[CH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[CH:27][CH:26]=2)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Oc1ccc2cc(Br)c(OCc3ccccc3)cc2c1
Reactant: BrCCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Brc1cc2ccc(OCCCOCc3ccccc3)cc2cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 59.4 %

Procedure:
Following GENERAL METHOD 5-1 for phenol alkylation, Cs2CO3 (485 mg, 1.489 mmol) was added to a solution of 7-(benzyloxy)-6-bromonaphthalen-2-ol (490 mg, 1.489 mmol) in acetone (14.90 mL) at RT. The reaction mixture was stirred for 5 min then ((3-bromopropoxy)methyl)benzene (682 mg, 2.98 mmol) was added, followed by addition of NaI (446 mg, 2.98 mmol). The reaction mixture was heated to 60° C. and stirred overnight, then filtered, washed with acetone and concentrated in vacuo. The resulting residue was partitioned between Et2O (60 mL) and water (20 mL). After separation, the organic layer was washed with saturated aq. sodium sulfite solution (20 mL), 2 M Na2CO3, and brine. The organic layer was then dried over MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography (10-60% EtOAc/heptane) afforded 3-(benzyloxy)-6-(3-(benzyloxy)propoxy)-2-bromonaphthalene (422 mg, 0.884 mmol, 60% yield) as a white solid (eluting at 30% EtOAc). LCMS Rt=1.81 min (condition C); LCMS (M+1)=479.9.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[C:16]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:17]=1.C(O)C.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([O:12][CH2:16][CH3:17])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: N#Cc1cnc2cc(F)c(O)cc2c1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cc2c(Cl)c(C#N)cnc2cc1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 0° C. mixture of 4-chloro-7-fluoro-6-hydroxy-3-quinolinecarbonitrile (185 mg, 0.83 mmol), triphenylphosphine (392 mg, 1.49 mmol) and ethanol (153 mg, 3.32 mmol) in 15 mL of tetrahydrofuran is added diethylazodicarboxylate (260 mg, 1.80 mmol). The reaction mixture is kept at 0° C. for 45 minutes then stirred at room temperature overnight. The reaction mixture is concentrated in vacuo and purified by flash column chromatography eluting with a gradient of 1 % ethyl acetate in hexane to 5% ethyl acetate in hexane provides 4-chloro-6-ethoxy-7-fluoro-3-quinolinecarbonitrile, mp 165-166° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:16]4C(=O)C5=CC=CC=C5C4=O)=[CH:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[C:6]=2[CH:34]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH2:16])=[CH:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[C:6]=2[CH:34]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
A suspension of 8-chloro-1-(phthalimidomethyl)-6-(o-chlorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine (2.14g, 4.4 mmole) and hydrazine hydrate (1 g, 22 mmole) in 75ml. of absolute ethanol is stirred at room temperature under nitrogen for 20 hours. The white solid which precipitates is removed by filtration. Theethanol solution is evaporated to dryness in vacuo and the residue is dissolved in chloroform. The chloroform solution is washed with water, then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated in vacuo to give 1.56 g. (100%) of yellow oil. This oil is alkylated without any purification [example 37].
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH2:7][OH:8])[N:6]=1.C([OH:17])(C)C>CC(C)=O.S(=O)(=O)(O)O.O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[S:3][C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([C:7]([OH:17])=[O:8])[N:6]=1
Reactant: CC(C)O
Reactant: CCOC(=O)c1sc(Cl)nc1CO
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1sc(Cl)nc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of ethyl 2-chloro-4-(hydroxymethyl)-1,3-thiazole-5-carboxylate (2.5 g, 11 mmol, Intermediate 215) in acetone at 0° C. was slowly added a solution of chromium trioxide (2.26 g, 22 mmol) in 20% conc. Sulfuric acid in water (20 mL). After stirring at room temperature for 2 hrs, isopropanol (1 mL) was added to quench unreacted chromium trioxide. The reaction was diluted with water and the acetone was removed. Partitioning with methylene chloride (×3), drying with MgSO4 and concentrating yielded a white solid (2.3 g, 90%). MS (ES) MH+: 236 for C7H6ClNO4S; NMR: 1.26 (t, 3 H) 4.31 (q, 2 H) 13.99-14.15 (m, 1 H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C@H:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:16][C:17]([O:19][C@@H:20]3[CH:25]4[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]4)[CH2:21]3)=[O:18])[CH:10]=2)=[CH:5][C:4]([C:34](O)=[O:35])=[N:3]1.C(N(CC)CC)C.[CH2:44]([O:46][CH:47]([O:52][CH2:53][CH3:54])[CH2:48][CH2:49][CH2:50][NH2:51])[CH3:45].CCN=C=NCCCN(C)C.OC1C=CC=C[N+]=1[O-]>CN(C=O)C.C(OCC)(=O)C>[N:22]12[CH2:27][CH2:26][CH:25]([CH2:24][CH2:23]1)[C@@H:20]([O:19][C:17](=[O:18])[NH:16][C@H:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:6]3[N:2]([CH3:1])[N:3]=[C:4]([C:34](=[O:35])[NH:51][CH2:50][CH2:49][CH2:48][CH:47]([O:46][CH2:44][CH3:45])[O:52][CH2:53][CH3:54])[CH:5]=3)[CH:10]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:21]2
Reactant: CCOC(CCCN)OCC
Reactant: Cn1nc(C(=O)O)cc1COc1cccc([C@@H](NC(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: [O-][n+]1ccccc1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(CCCNC(=O)c1cc(COc2cccc([C@@H](NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)n(C)n1)OCC
Temperature: 25 °C
Reaction time: 90 h
Yield: 56.9 %

Procedure:
To a stirred solution of 1-methyl-5-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)-1H-pyrazole-3-carboxylic acid (0.30 g, 0.61 mmol) in DMF (6 mL) was added triethylamine (0.2 mL, 1.53 mmol), 4-aminobutyraldehyde diethyl acetal (0.20 mL, 1.22 mmol), EDCI (0.18 g, 0.91 mmol) and 2-hydroxypyridine-N-oxide (0.09 g, 0.91 mmol). The reaction mixture stirred at RT for 90 h. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate, brine, dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure to afford the crude target material (0.22 g, 57%) which was used directly without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1O[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:22])=[CH:10][CH:9]=2)=[O:4].COC(C1OC(=O)C2C(C=1C1C=CC(C)=CC=1)=CC=C(Cl)C=2)=O.[CH2:47]([NH:50][NH2:51])[CH2:48][OH:49].S(=O)(=O)(O)O>CO>[CH3:1][O:2][C:3]([C:5]1[N:51]([NH:50][CH2:47][CH2:48][OH:49])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)=[CH:12][C:11]([Cl:22])=[CH:10][CH:9]=2)=[O:4]
Reactant: NNCCO
Reactant: COC(=O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccc(C)cc1
Agent: COC(=O)c1oc(=O)c2cc(Cl)ccc2c1-c1ccc(C)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1c(-c2ccc(C)cc2)c2cc(Cl)ccc2c(=O)n1NCCO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution (5.0 ml) of 6-chloro-1-oxo-4-(p-tolyl)-1H-isochromen-3-carboxylic acid methyl ester and 7-chloro-1-oxo-4-p-tolyl-1H-isochromen-3-carboxylic acid methyl ester (mixture, 250 mg) in methanol was added hydrazine ethanol (540 μl), and the mixture was heated under reflux for 2 hrs. After cooling the reaction mixture, conc. sulfuric acid (0.5 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hrs. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=5/1-2/3) to give the title compound (50 mg) as colorless crystals.
Reaction SMILES: B(Cl)(Cl)Cl.[NH2:5][C:6]1[CH:11]=[CH:10][N:9]([CH:12]2[C@@H:16]([F:17])[C@H:15]([O:18]CC3C=CC(Cl)=CC=3)[C@@H:14]([CH2:27][O:28]CC3C=CC(Cl)=CC=3)[S:13]2)[C:8](=[O:37])[N:7]=1.CO>C(Cl)Cl>[NH2:5][C:6]1[CH:11]=[CH:10][N:9]([CH:12]2[S:13][C@H:14]([CH2:27][OH:28])[C@@H:15]([OH:18])[C@@H:16]2[F:17])[C:8](=[O:37])[N:7]=1
Reactant: Nc1ccn(C2S[C@H](COCc3ccc(Cl)cc3)[C@@H](OCc3ccc(Cl)cc3)[C@@H]2F)c(=O)n1
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: Nc1ccn(C2S[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)n1
Temperature: 0 °C
Yield: 72.4 %

Procedure:
In a nitrogen atmosphere, 6.8 mL of a methylene chloride solution of 1 mol/L boron trichloride was added to a solution of 0.17 g of (3S,4S,5R)-2-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorothiolane in 11 mL of methylene chloride under cooling on dry ice/acetone, and the obtained mixture was then stirred at the same temperature as described above for 3.5 hours. Thereafter, the temperature of the reaction mixture was increased to 0° C., and the reaction mixture was then stirred for 30 minutes. Thereafter, 7.5 mL of methanol was added to the reaction mixture, and the thus obtained mixture was then stirred at room temperature for 30 minutes. Thereafter, a solid was collected by filtration, and it was successively washed with ethyl acetate and hexane. The obtained solid was purified by silica gel column chromatography (chloroform/methanol=100/0 to 60/40), so as to obtain 63 mg of (2R,3S,4S)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-2-(hydroxymethyl)thiolan-3-ol in the form of a white solid.
Reaction SMILES: C[Si](C)(C)[N:3]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]([O:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:4]1=[O:18].C(N(CC)CC)C.CO>>[CH3:15][Si:14]([CH3:17])([CH3:16])[O:13][C@H:5]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:3][C:4]1=[O:18]
Reactant: C[Si](C)(C)OC1C(=O)N([Si](C)(C)C)C1c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: C[Si](C)(C)O[C@@H]1C(=O)N[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a solution of N-trimethylsilyl-3-trimethylsiloxy-4-phenyl-azetidin-2-one (140 g, 0.46 mol) in hexanes (600 mL) at ambient temperature was added triethylamine (101 g, 1 mol), methanol (22 g, 0.7 mol) and the mixture was stirred for 15 minutes resulting in crystal formation of the N-desilylated product. The mixture was cooled to 0° C. for 15 min and the white crystals were collected by vacuum filtration, washed with cold hexanes, and dried to a constant weight of 94 g (87% yield). Mp: 118 to 120° C., 1H NMR (400 MHz, CDCl3) δ (ppm): −0.08 (s, 9H), 4.79 (d, J=4.4 Hz, 1H), 5.09 (dd, J=4.4, 2.7 Hz, 1H), 6.16 (bm, 1H), 7.3 to 7.4 (m, 5H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:9])=[NH:8])([O-:3])=[O:2].[N+:13]([C:16]1[CH:27]=[CH:26][C:19]([CH:20]=[CH:21][S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([CH:20]=[CH:21][S:22]([NH:8][C:7](=[NH:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)(=[O:24])=[O:23])=[CH:26][CH:27]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(C=CS(=O)(=O)Cl)cc1
Reactant: N=C(N)c1cccc([N+](=O)[O-])c1
Product: N=C(NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1)c1cccc([N+](=O)[O-])c1

Procedure:
Reaction of 3-nitrobenzamidine with 4-nitrostyrylsulfonyl chloride according to the above procedure provides N-(4-NITROSTYRYLSULFONYL)-3-NITROBENZAMIDINE, m.p. 230°-232° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][O:11][CH2:12][C:13]([OH:15])=O)=[C:4]([C:17]([O:19]C)=[O:18])[CH:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH:32]1([NH:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C1COCC1.O.CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][O:11][CH2:12][C:13]([N:38]([CH:39]2[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]2)[CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:15])=[C:4]([CH:3]=1)[C:17]([OH:19])=[O:18]
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: O=C(COCC(=O)N(C1CCCCC1)C1CCCCC1)Nc1ccc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 g (3.3 mmol) of (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid, a catalytic quantity of DMF, and 505 mg (3.98 mmol) of oxalyl chloride were stirred at 0° C. for 1.5 hours in 10 mL of THF. After completion of the reaction, the solvent was distilled off under reduced pressure. 0.66 g (3.6 mmol) of dicyclohexylamine, and 10 mL of DMA were added to this residue, and stirred at room temperature for 2 hours. After completion of the reaction, water was added, and the precipitated crystals were collected by filtration and dried to give the crude product of 5-chloro-2-(([2-(dicyclohexylamino)-2-oxoethoxy]acetyl)amino)benzoic acid.methyl ester. The crude product was then used in the subsequent stage without being purified.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23]Br)=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH2:34]([NH2:37])[CH2:35][NH2:36]>CS(C)=O.ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:36][CH2:35][CH2:34][NH2:37])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: NCCN
Reactant: COc1cc(CC(=O)NCCCc2ccc(C)c(C)c2)ccc1OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cc(CC(=O)NCCCc2ccc(C)c(C)c2)ccc1OCCNCCN
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.9 %

Procedure:
0.35 g (0.81 mmol) of N-{3-(3,4-dimethylphenyl)propyl}-4-(2-bromoethoxy)-3-methoxyphenylacetamide obtained in step 1 of Example 2 was dissolved in 3 ml of dimethylsulfoxide and 0.56 g (4.02 mmol) of potassium carbonate was added thereto. To this mixture, 0.48 g (8.06 mmol) of ethylenediamine was slowly added at room temperature, followed by stirring at room temperature for 4 hours. The reaction mixture was diluted with 40 ml of dichloromethane, washed with water and acidified with 1N HCl and the aqueous layer was separated. The aqueous layer was basified with hydrogen peroxide, extracted with 40 ml of dichloromethane, dried and the solvent was removed under a reduced pressure. The residue was triturated with a mixture of dichloromethane and hexane(1:2) to obtain 0.10 g of the title compound as a white solid(yield: 30%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.C([O-])([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O.O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:13]2[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc(Cl)nn2)cn1
Temperature: 80 °C
Yield: 54.6 %

Procedure:
A flask was charged with 3,6-dichloropyridazine (Aldrich, 23.91 g, 160.5 mmol), 1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (20 g, 96 mmol), 2.0 M Na2CO3 (96 mL) and dioxane (65 mL). Nitrogen was bubbled through the reaction for 60 seconds followed by the addition of Dichlorobis(triphenylphosphine)palladium (0) (6.75 g, 9.6 mmol). The reaction was heated to 80° C. overnight followed by aqueous work up using AcOEt and a solution of K2CO3. After filtration over celite, the organic layer was dried (MgSO4) and concentrated in vacuo. A first fraction of compound (10.2 g) was obtained by crystallization in the solvent (dichoromethane). The filtrate was purified by column chromatography (CH2Cl2 100% and CH2Cl2/MeOH: 95/5). The two fractions were gathered and washed with diisopropylether to give the title compound as a yellow solid (12.7 g, 68%).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2([OH:31])[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1>>[OH:31][C:25]1([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=2)[CH2:30][CH2:29][CH2:28][N:27]([C:8](=[O:9])[CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:26]1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: COc1cccc(C2(O)CCCN(C(=O)C(c3ccccc3)c3ccccc3)C2)c1

Procedure:
The compound of Example 29 was prepared according to the general preparation protocol A from diphenylacetyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:30])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:27]([NH2:29])=[O:28])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:31]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[C:34](=O)[O:33][C:32]1=O.COC(OC)OC.O.O.O.O.O.O.[N+]([O-])([O-])=O.[La+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C1COCC1>[CH3:30][C:3]1[C:2]([N:1]2[C:34](=[O:33])[C:35]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:31]=[CH:32]2)=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:27]([NH2:29])=[O:28])=[N:10][CH:9]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Cc1c(N)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(N4CCOCC4)ccc3c12
Agent: O=[N+]([O-])[O-]
Agent: [La+3]
Solvent: C1CCOC1
Solvent: COC(OC)OC
Solvent: O
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(N5CCOCC5)ccc4c23)cccc1-n1cnc2ccccc2c1=O
Temperature: 25 °C
Yield: 17.1 %

Procedure:
A burgundy solution of 4-(3-amino-2-methylphenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide (0.0612 g, 0.140 mmol), 1H-benzo[d][1,3]oxazine-2,4-dione (0.057 g, 0.351 mmol), trimethoxymethane (0.154 ml, 1.402 mmol) and lanthanum nitrate hexahydrate (0.018 g, 0.042 mmol) in THF (0.334 mL) in a sealed vial was stirred overnight at 95° C. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in DMSO (0.2 mL) and MeOH (1.6 mL), and subjected to autoprep reverse phase HPLC. The appropriate fractions were collected, basified with NaHCO3 (solid), and concentrated in vacuo. The residue was extracted with CH2Cl2 (3×). The combine extract was dried over Na2SO4 and concentrated in vacuo to give the desired product (0.0135 g, 0.024 mmol, 17.1% yield) as a tan solid. LC/MS (M+H)=531.29; 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for major atropoisomer) δ ppm 11.48 (1 H, s), 8.42 (1 H, s), 8.21-8.28 (2 H, m), 8.15 (1 H, s), 7.88-7.94 (1 H, m), 7.76-7.81 (1 H, m), 7.69-7.74 (1 H, m), 7.53-7.69 (4 H, m), 7.27 (1 H, d, J=2.22 Hz), 6.79-6.86 (1 H, m), 3.74-3.81 (4 H, m), 3.16-3.23 (4 H, m), 1.81 (3 H, s).