Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[O:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][NH:45][CH2:46][CH3:47]>CN(C=O)C>[CH2:46]([N:45]([CH2:44][CH:40]1[CH2:41][CH2:42][CH2:43][O:39]1)[C:16]1[C:17]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:21][CH2:20][C:18]=2[N:19]=[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])=[CH:12][CH:11]=2)[N:15]=1)[CH3:47]
Reactant: CCNCC1CCCO1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: CN(C)C=O
Product: CCN(CC1CCCO1)c1nc(Nc2ccc(-n3ccnc3C)cc2)nc2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 85 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-(4-(2-methyl-1H- imidazol-1-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (250 mg, 0.45 mmol, example 69c) was dissolved in DMF (2 mL). N-((tetrahydrofuran-2-yl)methyl)ethanamine (58.2 mg, 0.45 mmol) was added and the reaction mixture was stirred at 85° C. overnight. The reaction was allowed to reach room temperature, the solvent was evaporated under reduced pressure and the crude was used as such in the subsequent step. MS (ES+) m/z 534.4 (M+H)+
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:7][N:8]([C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)[C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCC(=O)N(C)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a stirred solution of butyryl chloride (0.770 g, 7.23 mmol) in chloroform ( 15 mL) was added N-methyl-4-nitroaniline and triethylamine (1.2 mL, 8.6 mmol). After overnight stirring, additional butyryl chloride (0.40 mL, 3.9 mmol) was added and the reaction was refluxed for 2-3 hours. The reaction was concentrated and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was combined with a second ethyl acetate extract, dried (sodium sulfate) and concentrated. The resulting dirty yellow oil was purified by flash chromatography over silica (methylene chloride/methanol) to afford 1.11 g (76%) of product as a pale yellow solid: 1H NMR (CDCl3) δ 8.30 (d, J=8.9 Hz, 1H), 7.40 (d, J=8.9 Hz, 1H), 3.34 (s, 3H), 2.18 (t, J=7.5 Hz, 2H), 1.71-1.59 (m, 2H), 0.88 (t, J=7.6Hz,
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][C:26]3=[O:30])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:31])[CH3:9])=[CH:4][CH:3]=1.[CH3:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1>>[CH3:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][C:26]4=[O:30])([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:12][C:11]3=[O:31])[CH3:9])=[CH:4][CH:3]=2)[CH:36]=[CH:35][N:34]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCN2CCCC2=O)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCN4CCCC4=O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-(2-oxopyrrolidin-1-yl)propyl)-6-phenyl-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 459 Step 1. LC-MS Method 2 tR=0.992, m/z=498.1; 1H NMR (CDCl3) 1.21 (m, 3H), 1.48 (d, 3H), 1.61-1.95 (m, 5H), 2.12 (m, 1H), 2.26 (m, 4H), 2.52 (s, 3H), 2.83 (m, 1H), 3.11 (m, 3H), 3.22 (m, 1H), 5.67 (m, 1H), 6.95 (d, 2H), 7.18 (m, 1H), 7.21 (m, 1H), 7.23 (m, 2H), 7.29 (m, 3H), 7.30 (m, 2H), 8.41 (d, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:16])[CH:12]=2)[CH:7]=1)=[O:5])C.[OH-].[Na+].O>C(O)C>[F:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:15]=[CH:14]2
Reactant: CCOC(=O)c1ccc2cc(F)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6-fluoro-2-naphthoic acid ethyl ester (600 mg, 2.75 mmol) in ethanol (10 mL) at room temperature, is added 1 N NaOH (2.75 mL, 2.75 mmol). After stirring at room temperature for 4 hours, water (10 mL) is added. Acidification (2 N HCl) and filtration gives 6-fluoro-2-naphthoic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH2:16])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH:16][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C(=O)Nc2cccc(Cl)c2)c(N)s1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: Cc1nc(C(=O)Nc2cccc(Cl)c2)c(NC(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.7 %

Procedure:
A solution of 5-amino-2-methyl-thiazole-4-carboxylic acid (3-chloro-phenyl)-amide (0.04 g, 0.17 mmol) in dry dioxane (0.50 ml) and pyridine (0.02 ml) was cooled to 0° C. and treated with benzoyl chloride (0.02 g, 0.17 mmol). The mixture was then left to warm to room temperature and stirred overnight. After evaporation of the solvent, the residue was triturated in acetonitrile to yield the title compound (0.003 g, 4%) as a white solid, MS (ISP): m/e=372.3 (M+H+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:35])[O:14][CH2:15][C@@H:16]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:5]2.CCN(C(C)C)C(C)C.[N:45]([CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[C:46]=[O:47]>C1COCC1>[Cl:33][C:27]1[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][NH:24][C:22](=[O:23])[N:21]([CH3:34])[C@H:16]([CH2:15][O:14][C:13](=[O:35])[NH:12][C:6]1[N:7]=[CH:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)[CH2:17][CH2:18][CH2:19][NH:20][C:46](=[O:47])[NH:45][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50]
Reactant: CCOC(=O)CN=C=O
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN)COC(=O)Nc1cc2cc(F)ccc2cn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)NCCC[C@@H](COC(=O)Nc1cc2cc(F)ccc2cn1)N(C)C(=O)NCc1cccc(F)c1Cl
Yield: 79.5 %

Procedure:
To a mixture of (S)-5-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentyl 6-fluoroisoquinolin-3-ylcarbamate (0.40 g, 0.792 mmol), DIEA (0.276 mL, 1.58 mmol) and THF (2 mL), ethyl isocyanatoacetate (0.108 mL, 0.950 mmol) was added. The mixture was refluxed for 30 min, and concentrated. The remaining residue was purified on silica gel column (DCM/MeOH) to give (S)-ethyl 1-(2-chloro-3-fluorophenyl)-5-((6-fluoroisoquinolin-3-ylcarbamoyloxy)methyl)-4-methyl-3,10-dioxo-2,4,9,11-tetraazatridecan-13-oate (0.40 g, 80%). LRMS (M+H+) m/z 635.6.
Reaction SMILES: Br[C:2]1[C:3]2[N:4](N=N[N:23]=2)[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.CC(C)([O-])C.[K+].O1CCOCC1>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>[NH2:23][C:3]1[C:2]([C:25]2[S:24][CH:28]=[CH:27][CH:26]=2)=[CH:7][N:6]=[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=1
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)c3nnnn23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)c(N)n2)CC1
Temperature: 80 °C
Reaction time: 10 h
Yield: 8.7 %

Procedure:
A 500 mL round bottom flask was charged with tert-butyl 4-(8-bromotetrazolo[1,5-c]pyrimidin-5-yl)piperazine-1-carboxylate (5.5 g, 14.3 mmol), thiophene-2-boronic acid (2.5 g, 21.5 mmol), tetrakis(triphenylphosphine)palladium(0) (2.0 g, 1.43 mmol), potassium tert-butoxide (2.4 g, 21.5 mmol), 1,4-dioxane (200 mL) and water (50 mL). After the air was purged by bubbling N2 into the solution, the resulting mixture was stirred at 80° C. under N2 for 10 h. Work-up: the reaction mixture was diluted with 0.1 M HCl (20 mL) and washed with EtOAc (150 mL×3). The aqueous layer was then basified with solid NaHCO3 and extracted with CH2Cl2 (150 mL×3). The combined CH2Cl2 layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 1-10% MeOH in CH2Cl2 to afford 0.70 g (12%) of the product, and 0.45 g (8.7%) of tert-butyl 4-(4-amino-5-(thiophen-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1)[CH:5]=O.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24]C1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1)[CH2:5][N:22]1[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: Cc1cc(C=O)ccc1N1CCC(CN2CCCC2)CC1
Reactant: C1CCNCC1
Product: Cc1cc(CN2CCCC2)ccc1N1CCC(CN2CCCC2)CC1

Procedure:
Prepared from the product of Example 66 and piperidine.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:25]([C:32]2[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=2)=[CH:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:27]1([CH:26]=[C:25]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([O:19][CH2:20][CH2:21][N:22]([CH3:23])[CH3:24])[CH:18]=[C:13]3[CH:12]=2)[C:32]2[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CN(C)CCOc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CCOc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 74.7 %

Procedure:
A solution of (2-{1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-ethyl)-dimethyl-amine (350 mg, 0.59 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 4 mL, 4 mmol) was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (150 mL), and washed with a saturated aqueous ammonium chloride solution, brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford (2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-ethyl)-dimethyl-amine (200 mg, 75%) as a white solid: LC/MS m/e calcd for C25H31N3O3S [M+H]+ 454.61, observed 454.1.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:25]I>>[CH3:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])[CH3:25])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CI
Reactant: COc1cc(OC)c(Nc2nc(C)nc3ccccc23)c(OC)c1
Product: COc1cc(OC)c(N(C)c2nc(C)nc3ccccc23)c(OC)c1

Procedure:
The title compound was prepared from (2-methyl-quinazolin-4-yl)-(2,4,6-trimethoxy-phenyl)-amine (56 mg, 0.17 mmol) and methyl iodide (0.1 ml, 1.6 mmol) by a procedure similar to Example 36. 1H NMR (CDCl3): 7.70 (d, J=8.4 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.09 (d, J=8.7 Hz, 1H), 6.93 (t, J=8.1 Hz, 1H), 6.18 (s, 2H), 3.86 (s, 3H), 3.63 (s, 6H), 3.44 (s, 3H), 2.70 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([CH2:12][N:13]([C:21]3[N:22]=[N:23][C:24]([C:27]4[S:28][CH:29]=[CH:30][N:31]=4)=[CH:25][CH:26]=3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:39])C(=O)C1.CN(C=O)C>C(OCC)(=O)C>[Br:39][C:29]1[S:28][C:27]([C:24]2[N:23]=[N:22][C:21]([N:13]([CH2:12][C:8]3([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[CH2:11][CH2:10][CH2:9]3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:26][CH:25]=2)=[N:31][CH:30]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2nccs2)nn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(Br)s2)nn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a 100 mL round bottom flask was added t-butyl (1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(thiazol-2-yl)pyridazin-3-yl)carbamate (2.0 g, 4.6 mmol), NBS (1.6 g, 9.1 mmol), and DMF (20 mL). The reaction was heated to 100° C. and stirred overnight. The reaction mixture was then was poured into ethyl acetate (200 mL), washed with water (100 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (EtOAc/hex) to afford 1.8 g of t-butyl 6-(5-bromothiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:11][C:12]1[CH:29]=[CH:28][C:15]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23](=[O:27])[C:24](O)=[O:25])[CH2:19][CH2:18]2)=[CH:14][CH:13]=1>C(OCC)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:24](=[O:25])[C:23]([N:20]3[CH2:19][CH2:18][CH:17]([CH2:16][C:15]4[CH:14]=[CH:13][C:12]([F:11])=[CH:29][CH:28]=4)[CH2:22][CH2:21]3)=[O:27])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc2[nH]cnc2c1
Solvent: CCOCC
Product: O=C(Nc1ccc2[nH]cnc2c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from (1H-benzimidazol-5yl) amine [Synth. Commun., 29, 2435. (1999)] and [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid Example 1b) according to the method described in Example 1c. Melting Point: 104-110° C. (diethylether)
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([NH2:22])[CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[NH2:11][C:12]1[CH:21]=[C:20]([NH:22][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:19]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=1
Reactant: COC(=O)c1cc(N)cc(N)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(N)cc(Nc2ncccc2[N+](=O)[O-])c1
Yield: 20.2 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (3.20 g), methyl 3,5-diaminobenzoate (3.20 g) and potassium carbonate (4.0 g) in 1,4-dioxane (60 ml) was stirred under reflux for 4 hours. After cooling, insoluble materials were removed by filtration and the filtrate was concentrated. The residue was chromatographed on silica gel column (5% methanol in chloroform) to give 2-(3-amino-5-methoxycarbonylphenylamino)-3-nitropyridine (1.12 g).
Reaction SMILES: [S:1]([CH2:7][CH2:8][C:9](O)=O)[CH2:2][CH2:3][C:4](O)=O.[NH2:12][NH:13][C:14]([NH2:16])=[S:15]>O=P(Cl)(Cl)Cl>[S:1]([CH2:7][CH2:8][C:9]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1)[CH2:2][CH2:3][C:4]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1
Reactant: O=C(O)CCSCCC(=O)O
Reactant: NNC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nnc(CCSCCc2nnc(N)s2)s1
Temperature: 90 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A mixture of 3,3′-thiodipropanoic acid (1 equivalent) and thiosemicarbazide (2 equivalents) were taken in POCl3 (10 fold) and stirred at 90° C. for 3 h. The reaction mixture was cooled to room temperature and poured on to ice. The resulting mixture was filtered and then brought to pH 14 using KOH. The white solid that was formed was filtered, washed with water and dried to afford the desired product I-2 in 50-60% yield. This material was used as such for the next step.
Reaction SMILES: [CH:1]([N:4]([CH:30]([CH3:32])[CH3:31])[CH2:5][CH2:6][C@H:7]([C:14]1[CH:19]=[C:18]([CH:20]=[CH2:21])[CH:17]=[CH:16][C:15]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].B1C2CCCC1CCC2.[OH-:42].[Na+].OO>C1COCC1.O>[CH:30]([N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6][C@H:7]([C:14]1[CH:19]=[C:18]([CH2:20][CH2:21][OH:42])[CH:17]=[CH:16][C:15]=1[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:32])[CH3:31]
Reactant: C=Cc1ccc(OCc2ccccc2)c([C@@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(CC[C@@H](c1ccccc1)c1cc(CCO)ccc1OCc1ccccc1)C(C)C
Temperature: 25 °C

Procedure:
(S)-N,N-Diisopropyl-3-(2-benzyloxy-5-ethenylphenyl)-3-phenylpropanamine (1 g, 2.34 mmol) in THF (25 mL) was added to 9-BBN (0.5 M in THF, 11.7 mL, 5.85 mmol) under nitrogen atmosphere at 0° C. Additional 9-BBN (2.3 mL, 1.2 mmol) was added after 3 hours of stirring, the temperature was raised to room temperature and the mixture was stirred for 0.5 hour. It was then cooled to 0° C. and 1 M sodium hydroxide (10 mL) was added followed by H2O2 (30% in H2O, 10 mL). After 1 hours stirring, water was added and the mixture was extracted with diethyl ether. The organic layer was washed with water and brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica (gradient of diethyl ether to 1% NH3 in diethyl ether). Yield 0.67 g (64%). 1H NMR (CDCl3) δ0.90 (d, 12H), 2.10-2.18 (m, 2H), 2.30-2.37 (m, 2H), 2.80 (t, 2H), 2.90-3.0 (m, 2H), 3.80 (br, 2H), 4.40 (t, 1H), 5.0 (s, 2H), 6.80 (d, 1H), 7.0 (m, 1H), 7.10-7.38 (m, 11H).
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:13]=2[OH:21])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl>O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]2[O:21][C:13]3[C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)=[CH:22][CH:23]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cccc([N+](=O)[O-])c2O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(-c2nc3cccc([N+](=O)[O-])c3o2)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
A solution of 4-tert-butyl-N-(2-hydroxy-3-nitrophenyl)benzamide (0.35 g, 1.11 mmol) and pyridinium p-toluenesulfonate (200 mg, 0.8 mmol) in xylenes (25 mL) was heated in a 135° C. bath for 72 h. The solution was cooled to room temperature, and CH2Cl2 (100 mL) and H2O (25 mL) were added. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford the title compound (0.260 g) as a golden solid. MS (ESI-POS): [M+H]+=297; Anal. Calcd for C17H16N2O3: C, 68.91; H, 5.44; N, 9.45. Found: C, 69.02; H, 5.43; N, 9.00.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]1[O:22][CH2:21]1.O>CO>[OH:22][CH2:21][CH2:20][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:13][CH2:12][CH2:11]1
Reactant: C1CO1
Reactant: c1ccc(C2(c3ccccc3)CCNCCO2)cc1
Solvent: CO
Solvent: O
Product: OCCN1CCOC(c2ccccc2)(c2ccccc2)CC1
Reaction time: 2 h

Procedure:
The mixture of 6.5 g of 7,7-diphenyl-hexahydro-1,4-oxazepine, 1.2 g of ethylene oxide, 0.5 ml of water and 20 ml of methanol is stirred at 40°-45° for 4 hours and at 50° for 21/2 hours. It is cooled, the precipitate formed, filtered off and recrystallized from benzene-hexane, to yield the 4-(2-hydroxyethyl)-7,7-diphenyl-hexahydro-1,4-oxazepine melting at 122°-123° (its hydrochloride melts at 190°-192°).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12](=[CH2:16])[C:13]([OH:15])=O)=[CH:7][CH:6]=1)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[C:48]([Br:49])=[CH:47][CH:46]=[CH:45][N+:44]=1[O-:50].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:49][C:48]1[C:43]([NH:42][C:13](=[O:15])[C:12](=[CH2:16])[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=2)[CH3:17])=[N+:44]([O-:50])[CH:45]=[CH:46][CH:47]=1
Reactant: C=C(C(=O)O)C(C)c1ccc(C(=O)OC)cc1
Reactant: Nc1c(Br)ccc[n+]1[O-]
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
Product: C=C(C(=O)Nc1c(Br)ccc[n+]1[O-])C(C)c1ccc(C(=O)OC)cc1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(4-(methoxycarbonyl)phenyl)-2-methylenebutanoic acid (1.0 g, 4.2 mmol), HATU (1.9 g, 5.1 mmol), 2-amino-3-bromopyridine 1-oxide (0.88 g, 4.6 mmol) and diisopropyl ethylamine (2.22 mL, 12.5 mmol) in anhydrous DMF (10 mL) was stirred at 23° C. for 1 h, then concentrated. The residue was partitioned between ethyl acetate and brine (2×). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated. The residue was triturated with acetonitrile (20 mL). The solid was filtered and dried under vacuum to give the title compound. MS: m/z=406.0 (M+1).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:22]([O-:24])=[O:23])=[C:6]([CH2:8][S:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.[CH2:25]([OH:28])[CH2:26][OH:27].C1COCC1>CC(C)([O-])C.[K+]>[C:12]1([S:9]([CH2:8][C:6]2[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=2[N+:22]([O-:24])=[O:23])[O:27][CH2:26][CH2:25][OH:28])(=[O:11])=[O:10])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1CS(=O)(=O)c1cccc2ccccc12
Reactant: OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCCO)cc1CS(=O)(=O)c1cccc2ccccc12
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A mixture of 1-(5-fluoro-2-nitro-phenylmethanesulfonyl)-naphthalene (14.6 g, 42.3 mmol) and ethylene glycol (35 mL, 630 mmol) in 1.0 N potassium tert-butoxide in THF (90 mL, 90 mmol) was refluxed under nitrogen for one hour. After cooling to ambient temperature, the reaction mixture was concentrated. Excess water was added to the residue, and the mixture was poured into ice/2N hydrochloric acid. It was extracted with ethyl acetate and washed with water and brine. It was then dried with anhydrous magnesium sulfate, filtered, concentrated and dried in vacuo at 80° C. for 25 minutes to yield 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-ethanol as a brown gum (14.3 g, 87.2%). Mass Spectrum (−EI, [M−H]−) m/z 386. 1HNMR (500 MHz, DMSO-d6): δ8.56-8.57 (m, 1H), 8.35 (d, 1H, J=8.24 Hz), 8.14-8.15 (m, 1H), 8.00-8.02 (m, 2H), 7.65-7.75 (m, 3H), 7.11-7.13 (m, 1H), 6.89 (d, 1H, J=2.90 Hz), 5.27 (s, 2H), 4.92 (t, 1H, J=5.49 Hz), 3.93-3.95 (m, 2H), 3.67 ppm (dd, 2H, J=9.91 Hz and 5.34 Hz). Elemental Analysis for C19H17NO6S.0.25 mol H2O: Calcd: C, 58.23; H, 4.50; N, 3.57; Found: C, 57.83; H, 4.25; N, 3.50.