Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:49]1([C:54](Cl)=[O:55])[CH2:53][CH2:52][CH2:51][CH2:50]1>>[N:49]1([C:54]([O:39][C@H:36]2[CH2:37][CH2:38][C@H:33]([C:30]3[CH:31]=[CH:32][C:27]([C:23]4[N:22]=[C:21]5[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:18]([O:17][C@@H:16]6[CH2:15][O:14][C@@H:13]7[C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:10][O:11][C@H:12]67)=[N:19][C:20]5=[CH:25][C:24]=4[Cl:26])=[CH:28][CH:29]=3)[CH2:34][CH2:35]2)=[O:55])[CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: O=C(Cl)N1CCCC1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](OC(=O)N5CCCC5)CC4)cc3)nc2n1COCC[Si](C)(C)C
Temperature: 100 °C

Procedure:
The title compound is prepared from (trans)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanol and pyrrolidine-1-carbonyl chloride following a procedure analogous to that described for Intermediate 12 Step 2 but heating the mixture for 48 hours at 100° C. LC (method 5): tR=1.32 min.
Reaction SMILES: [CH2:1]([N:5](C(OC(C)(C)C)=O)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][CH:3]=[CH2:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([NH:5][C:6](=[O:7])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCCNC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 95.8 %

Procedure:
To a solution of 186 (708 mg, 2.61 mmol) in DCM (20 mL) was added trifluoroacetic acid (593 mg, 5.20 mmol) and the mixture was allowed to stir for 5 min before being quenched with 2M NaOH (25 mL) and extracted with DCM (3×20 mL). The combined organic fractions were dried, and concentrated to yield the title compound (429 mg, 2.50 mmol, 96%) as a light brown oil, which had spectral data in agreement with that reported.104 1H NMR (CDCl3, 300 MHz): δ 5.75 (m, 1H, H3); 5.08 (m, 2H, H4); 4.59 (bs, 1H, NH); 3.20 (dd, J=6.3, 12.6 Hz, 2H, H1); 2.24 (dd, J=6.9, 12.6 Hz, 2H, H2); 1.44 (s, 9H, (CH3)3). Mass Spectrum (ES, +ve) m/z 116 (100%) [MH+] less 56 (Boc rearrangement].
Reaction SMILES: [C:1]1(B2OC(C)(C)C(C)(C)O2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.I[C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].[OH-].[K+]>O1CCOCC1.O>[C:1]1([C:17]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(C2=CCCCC2)c(C(=O)O)c1

Procedure:
In analogy to a procedure described by Masuda et al. [M. Murata, T. Oyama, S. Watanabe, Y. Masuda, Synthesis 2000, 778] a stirred mixture of 1 eq. 2-cyclohex-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, 0.8 eq. 2-iodo-5-methanesulfonyl-benzoic acid, 2 eq. aqueous 3M KOH solution and 0.03 eq PdCl2 (dppf)2-CHCl3 in dioxane (0.2 ml per mmol) were heated to 80° C. for 5 h. Then the reaction mixture is diluted with water, extracted with AcOEt, the aqueous phase acidified with 2N H2SO4, extracted with AcOEt and the pooled organic extracts dried over Na2SO4, filtered and evaporated. The crude product is purified by flash-chromatography on silica gel with heptane/AcOEt as eluent to yield the title compound; MS (ISN): 279.8 M−H−.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:22])=O>ClCCl.CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:22])=[O:15])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a suspension of 4-{[(tert-butoxycarbonyl)amino]methyl}benzoic acid of Step A (3.55 g, 0.0141 mmol) in dry dichloromethane (40 mL) at room temperature under nitrogen was added dry N,N-dimethylformamide (2 drops, cat.) followed by a 2.0 M solution of oxalyl chloride in dichloromethane (14.1 mL, 0.0283 mol) and the reaction mixture stirred at room temperature for 4.5 hours. The reaction mixture was then concentrated in vacuo to afford (4-chlorocarbonyl-benzyl)carbamic acid tert-butyl ester as a white solid. The crude acid chloride was dissolved in dry tetrahydrofuran (20 mL), added to a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 76, Step C (3 g, 9.42 mmol), and N,N-diisopropylethylamine (4.92 mL, 28.27 mmol) in dry tetrahydrofuran (20 mL), and the reaction mixture stirred at room temperature for 19 hours. The reaction was quenched by the addition of 2 M sodium hydroxide (20 mL) and then partitioned between ethyl acetate (200 mL) and 2 M sodium hydroxide (200 mL). The separated organic phase was washed with 2 M sodium hydroxide (200 mL), water (200 mL) and brine (200 mL), dried over magnesium sulfate, and concentrated in vacuo to afford an orange solid (3.95 g). Purification by flash chromatography using a solvent gradient of 1 to 5% methanol in dichloromethane gave a colorless glass that was recrystallized from ethyl acetate/hexane to afford the title compound (1.29 g, 25%) as a cream crystalline solid, m.p. 171° C.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:30]=[CH:29][C:9]([CH2:10][N:11]3[C:27](=[O:28])[N:14]4[N:15]=[CH:16][C:17]([C:20]5[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=5)=[C:18](Cl)[C:13]4=[N:12]3)=[CH:8][CH:7]=2)=[CH:4][CH:3]=[N:2]1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]1[C:5]([C:6]2[CH:30]=[CH:29][C:9]([CH2:10][N:11]3[C:27](=[O:28])[N:14]4[N:15]=[CH:16][C:17]([C:20]5[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=5)=[C:18]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:13]4=[N:12]3)=[CH:8][CH:7]=2)=[CH:4][CH:3]=[N:2]1
Reactant: O=c1n(Cc2ccc(-c3ccno3)cc2)nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1n(Cc2ccc(-c3ccno3)cc2)nc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 25 °C
Yield: 14 %

Procedure:
To a stirred solution of 2-(4-(isoxazol-5-yl)benzyl)-8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (100 mg, 0.23 mmol), prepared as described in Example 355 in toluene (2 mL) in a round bottomed flask was added Pd(PPh3)4 (16 mg, 0.014 mmol) under bubbling argon. Phenyl boronic acid (36 mg, 0.3 mmol) was added subsequently. Under vigorous stirring, Na2CO3 (97 mg, 0.91 mmol) pre-dissolved in water (0.25 mL) was added to the suspension. Argon was bubbled through this suspension for 10 min before the flask was placed in an oil bath preheated at 120° C. The reaction was stirred at reflux for 6 days. The reaction was then allowed to cool to RT. After this time, the reaction mixture was poured into water (10 mL). The resultant solution was extracted with EtOAc (3×10 mL). The combined organic layers were washed with water (2×10 mL) followed by saturated aqueous NaCl (2×5 mL). The organic layer was dried (MgSO4), filtered and concentrated to obtain crude product. This crude product was purified by reverse phase HPLC to give the title compound, 2-(4-(isoxazol-5-yl)benzyl)-7-(4-chlorophenyl)-8-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (15.5 mg, 14%) as pale yellow solid. HPLC: 3.68 min; MS, M+H=480; 1H NMR (CDCl3), ppm: 8.31 (1H, d, J=2.0 Hz), 8.22 (1H, s), 7.77 (2H, d, J=10.0 Hz), 7.51 (2H, d, J=10.0 Hz), 7.26-7.42 (7H, m), 7.09 (2H, d, J=10.0 Hz), 6.54 (1H, d, J=5.0 Hz), 5.29 (2H, s).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:3][OH:4].Cl.[OH-].[K+].[C:14](=O)(OC(Cl)(Cl)Cl)[O:15]C(Cl)(Cl)Cl>O.C1COCC1>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:2]1[CH2:3][O:4][C:14](=[O:15])[NH:1]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC(CO)c1ccccn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1NC(c2ccccn2)CO1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 30.4 %

Procedure:
To a solution of 2-amino-2-(pyridin-2-yl)ethanol (3.8 g, 28 mmol) (as the bis HCl salt) in water (50 mL) cooled to 0° C. was added potassium hydroxide (11 g, 19 mmol) followed by THF (50 mL) and the reaction stirred for 20 minutes at 0° C., followed by addition of bis(trichloromethyl) carbonate (8.2 g, 28 mmol) as the solid and stirring at 0° C. for 2 hours. The reaction was next poured into water and extracted with EtOAc and the combined organic layers were washed with 1N NaOH, brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by normal phase chromatography using EtOAc as eluent to yield 4-(pyridin-2-yl)oxazolidin-2-one (1.4 g, 8.5 mmol, 31% yield).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36](O)=[O:37])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[NH:51][CH:52]=[CH:53][N:54]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([NH:49][C:50]2[NH:51][CH:52]=[CH:53][N:54]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Nc1ncc[nH]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1ncc[nH]1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Yield: 90.8 %

Procedure:
BOP coupling of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 1, Step A; 287 mg; 1.00 mmol) and 2-aminoimidazole (241 mg; 1.79 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 1, Step B) provided after flash chromatography (Biotage 40M; eluent: 4% methanol/methylene chloride) 320 mg of (S)-3-Cyclohexyl-N-(1H-imidazol-2-yl)-2-(1-oxo-1,3-dihydro-isoindol-2-yl) propionamide which was then recrystallized from ethyl acetate/hexanes to give 209 mg of pure material: EI-HRMS m/e calcd for C20H24N4O2 (M+) 352.1899, found 352.1895.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[NH:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]2=[O:43])[CH2:29][CH2:28]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C:12]([CH2:13][C:14](=[O:15])[N:27]1[CH2:28][CH2:29][CH:30]([N:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]2=[O:43])[CH2:31][CH2:32]1)([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:2]
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: CCOC(=O)C(CC(=O)O)(Cc1ccc(CC)c(CC)c1)C(=O)OCC
Product: CCOC(=O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)(Cc1ccc(CC)c(CC)c1)C(=O)OCC

Procedure:
Prepared analogously to Example 76c) from 4-(3,4-diethyl-phenyl)-3,3-bis-ethoxycarbonyl-butanoic acid and 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[NH:15]C(=O)C)([O-:3])=[O:2].O.[OH-].[Na+]>CO>[N+:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[NH2:15])([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccc(N2CCCC2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc(N2CCCC2)cc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 85 %

Procedure:
To a solution of N-(2-nitro-4-pyrrolidin-1-ylphenyl)acetamide obtained in step IV above (1.0 eq) in MeOH and water was added NaOH (1.5 eq) at room temperature and stirred for 5 hrs. Water was added to the reaction mixture and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired 2-nitro-4-pyrrolidin-1-ylaniline. (Yield=85%)
Reaction SMILES: O.[Si:2]([O:19][CH2:20][C@:21]12[C@H:27]([O:28]CC3C4C(=CC=CC=4)C=CC=3)[C@H:24]([O:25][CH2:26]1)[C@H:23]([N:40]1[CH:47]=[CH:46][C:44](=[O:45])[NH:43][C:41]1=[O:42])[O:22]2)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl>[Si:2]([O:19][CH2:20][C@:21]12[C@H:27]([OH:28])[C@H:24]([O:25][CH2:26]1)[C@H:23]([N:40]1[CH:47]=[CH:46][C:44](=[O:45])[NH:43][C:41]1=[O:42])[O:22]2)([C:15]([CH3:17])([CH3:16])[CH3:18])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)[Si](OC[C@]12CO[C@H]([C@H](n3ccc(=O)[nH]c3=O)O1)[C@H]2OCc1cccc2ccccc12)(c1ccccc1)c1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@]12CO[C@H]([C@H](n3ccc(=O)[nH]c3=O)O1)[C@H]2O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 96 %

Procedure:
Water (23 mL) was added to Compound 109 (11.8 g) dissolved in CH2Cl2 (120 mL) and the biphasic solution was stirred at room temperature. To this stirring solution was added DDQ (9.2 g) and the reaction mixture was stirred for 7 h at which point the reaction was complete. The reaction mixture was diluted with dichloromethane (500 mL) and it washed with 2% aqueous sodium bisulfite solution. The organic layer was separated and the aqueous layer was extracted several times with dichloromethane. The combined organic layer was washed with saturated sodium bicarbonate solution (5×300 mL). The organic layer was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The residue was purified by using 30% EtOAc in CH2Cl2 followed by 10% MeOH in CH2Cl2. Compound 110 obtained in a 96% yield as colorless pallets after removing the solvent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.Cl>Cl[Ni](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>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:1][O:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:13]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: Brc1cccnc1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: c1ccc(OCc2cccnc2)cc1

Procedure:
This substance was prepared by a dichlorobis-(triphenylphosphine)nickel (II) catalyzed reaction between 3-methoxyphenylmagnesium bromide (from 50 g of 3-bromo-anisole and 5.9 g of Mg in THF) and 31.8 g of 3-bromopyridine. Yield 23.1 g (62%), bp. 102°/0.15 mmHg, mp. (HCl) 187.5°-9° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[NH4+:20].[OH-]>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:20])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1cccc([N+](=O)[O-])c1Cl

Procedure:
DMF (3 drops) was added to a mixture of 2-chloro-3-nitrobezoic acid (0.99 g, 4.9 mmol), oxalyl chloride (0.47 mL, 5.4 mmol) in CH2Cl2 (20 mL) at 25° C. stirring under N2. After gas formation ceased, all the solid went into solution. After 3 hours the solvent was removed under reduced pressure to leave a light yellow solid which was treated with cold NH4OH (20 mL). 2-Chloro-3-nitrobenzamide was collected as an off-white solid (1.02 g, 100%).
Reaction SMILES: [Cl:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([N+:15]([O-:17])=[O:16])[CH:8]=1)[C:3]([OH:5])=[O:4].[C:18]1(C)C(S(O)(=O)=O)=CC=C[CH:23]=1>C(O)C>[Cl:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([N+:15]([O-:17])=[O:16])[CH:8]=1)[C:3]([O:5][CH2:18][CH3:23])=[O:4]
Reactant: COc1ccc(C[C@H](Cl)C(=O)O)cc1[N+](=O)[O-]
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H](Cl)Cc1ccc(OC)c([N+](=O)[O-])c1
Yield: 710.4 %

Procedure:
To a ethanol solution of (S)-2-chloro-3-(4-methoxy-3-nitrophenyl)propionicacid (4.46 g) was added p toluenesulfonicacid (0.38 g) and heated under reflux for 5 hours.After cooled it down, the solvent was evaporated in vacuo. Theresultant suspension solution was extracted by ethyl acetate (50 ml×3).After the ethyl acetate layer was washed with saturated brine,dried over anhydrous sodium sulfate. The solvent was evaporated invacuo, the resultant crude product was purified by silica gel columnchromatography, and eluted with mixture of hexane or ethylacetate (4:1, v/v). The fractions containing the desired productwere combined and evaporated in vacuo to obtain ethyl (S)-2-chloro-3-(4-methoxy-3-nitrophenyl)propionate(4.51 g)
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][C:4]1(N)[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]1[N+:11]([O-:13])=[O:12].Cl[C:18]([O:20][CH2:21][CH2:22][Cl:23])=[O:19].CCCCCC>O1CCOCC1>[Cl:23][CH2:22][CH2:21][O:20][C:18](=[O:19])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C:2]([F:16])([F:15])[F:1])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1
Reactant: O=C(Cl)OCCCl
Reactant: NC1=CC([N+](=O)[O-])C(N)(CC(F)(F)F)C=C1
Solvent: CCCCCC
Solvent: C1COCCO1
Product: O=C(Nc1ccc(CC(F)(F)F)c([N+](=O)[O-])c1)OCCCl
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A mixture of N1 -(2,2,2,-trifluoroethyl)-2-nitro-p-phenylene-diamine (6) (0.705 g, 3 mmol), 2-chloroethyl chloroformate (0.515 g, 3.6 mmol) and CaCo3 (0.40 g, 4 mmol) in dioxane (10 ml) was stirred at 80° C. for 20 minutes, filtered and washed with ethyl acetate. The combined filtrate was washed with water and brine, dried (Na2SO4), and evaporated to give a brown oil. Trituration with hexane gave 2-chloroethyl-N-[4-(2,2,2-trifluoroethyl)-3-nitrophenyl]-carbamate (8) as an orange solid. The unpurified carbamate (8) was dissolved in aqueous ethanol (ETOH: H2O, 15/5 ml) and powdered KOH (1.35 g) was added. The mixture was stirred at 90° C. for 20 minutes and then poured onto crushed ice (20 g) . The resultant mixture was extracted with ethyl acetate, washed with water and brine, dried (Na2SO4), and evaporated to give 0.544 g (65% yield) of N1 -(2,2,2-trifluoroethyl)-N4 -(2-hydroxyethyl)-2-nitro-p-phenylenediamine (9): mp 93°-95° C.; MS m/e 279(M+); 1HNMR (acetone-d6), δ3.25 (m, 2H), 3.76 (m, 2H), 3.91 (bs, 1H), 4.34 (m, 2H), 4.98 (bs, 1H), 7.19 (m, 2H), 7.35 (s,1H), 7.80 (bs, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[C:5](=[CH:12]/[C:13]1[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1)/[CH2:6][C:7]([O:9][CH2:10][CH3:11])=O)[CH3:2].C([O-])(=[O:23])C.[Na+]>C(OC(=O)C)(=O)C.O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([O:9][C:10](=[O:23])[CH3:11])[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[CH:12]=1)=[O:20])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)C/C(=C\c1cccc(C)c1)C(=O)OCC
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc(OC(C)=O)c2ccc(C)cc2c1
Temperature: 25 °C

Procedure:
To a solution of 2 g of 2-[1-m-Tolyl-meth-(E)-ylidene]-succinic acid diethyl ester in 10 ml of acetic acid anhydride, 594 mg sodium acetate was added and the reaction mixture was heated to reflux for 5 h. After cooling to RT the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed three times with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with n-heptane/ethyl acetate (1/1). The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 860 mg.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[C:16]([C:20]1[N:25]=[C:24]([O:26][CH3:27])[C:23]([CH:28]=[CH:29][C:30](O)=[O:31])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].CN1C(=O)CCC1>C1COCC1>[C:16]([C:20]1[N:25]=[C:24]([O:26][CH3:27])[C:23]([CH:28]=[CH:29][C:30]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[O:31])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1nc(C(C)(C)C)ccc1C=CC(=O)O
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COc1nc(C(C)(C)C)ccc1C=CC(=O)NCc1ccc(NS(C)(=O)=O)c(F)c1
Yield: 63 %

Procedure:
3-fluoro-4-methanesulfonylaminobenzylamine hydrochloride (17.8 mg, 0.052 mmol) was reacted with 3-(6-tert-butyl-2-methoxy-pyridin-3-yl)-acrylic acid (12 mg) DMTMM (1.1 eq, 16 mg) and NMP (1.2 eq, 90 μl) in THF to give the title compound (14 mg, 61.8%) after purification by column chromatography (Hex EtOAc=3/2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11](C(OC(C)(C)C)=O)[C:10]1[C:9](=[O:23])[CH2:8][CH2:7][CH2:6][C:5]2=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][C:10]1[C:9](=[O:23])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: CC(C)(C)OC(=O)n1c2c(c3cc(Cl)c(Cl)cc31)CCCC2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCCc2c1[nH]c1cc(Cl)c(Cl)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of tert-butyl 6,7-dichloro-1-oxo-3,4-dihydro-1H-carbazole-9(2H)-carboxylate (1.4 g, 3.9 mmol) in DCM (20 mL), cooled to 0° C., was added TFA (2 mL). The reaction mixture was stirred at 0° C. for 1 h, neutralized with saturated NaHCO3 (15 mL) and extracted with DCM (2×15 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a white solid (850 mg, 85%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.87 (bs, 1H), 7.75 (s, 1H), 7.55 (s, 1H), 2.98 (t, J=6.0 Hz, 2H), 2.68 (t, J=6.0 Hz, 2H), 2.30-2.25 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([C:29]3[CH:30]([CH3:36])[CH2:31][C:32](=[O:35])[NH:33][N:34]=3)=[CH:25][C:23]=2[N:24]=1>>[C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([C:29]3[CH:30]([CH3:36])[CH2:31][C:32](=[O:35])[NH:33][N:34]=3)=[CH:25][C:23]=2[N:24]=1)#[N:2]
Reactant: CC1CC(=O)NN=C1c1ccc2oc(NCCCCN)nc2c1
Reactant: N#Cc1ccccc1OCC1CO1
Product: CC1CC(=O)NN=C1c1ccc2oc(NCCCCNCC(O)COc3ccccc3C#N)nc2c1

Procedure:
Prepared analogously to Example 1 from 1-(2-cyanophenoxy)-2,3-epoxypropane and 6-[2-(4-aminobutylamino)benzoxazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.