Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CCOCC>[C:3]([C:2]1([C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:14][CH2:13]1)(=[O:4])[CH3:5]
Reactant: BrCCBr
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(=O)C1(C(=O)OC(C)(C)C)CC1
Temperature: 55 °C

Procedure:
Step 1 A stirred suspension of tert-butyl acetoacetate (2.1 mL, 12.6 mmol), 1,2-dibromoethane (1.14 mL, 13.3 mmol) and potassium carbonate (3.49 g, 25.3 mmol) in acetone (50.6 mL) was heated to 55° C. over a weekend. Upon cooling the mixture was diluted with Et2O and washed with water (×2). The organic phase was dried (Na2SO4), filtered and concentrated. Biotage column (40+M) eluting with a gradient of 0% Et2O/petrol to 20% Et2O/petrol gave tert-butyl 1-acetylcyclopropane-1-carboxylate, 0.78 g, 29%. 1H NMR (400 MHz, CDCl3): 2.46 (3H, s), 1.51 (9H, s), 1.43-1.38 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([OH:14])(=O)=[O:12].P(Cl)(Cl)(Cl)=O.[OH-].[NH4+:21].[OH-].[Na+].C>S1(CCCC1)(=O)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:21])(=[O:14])=[O:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Reactant: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 65.3 %

Procedure:
2-Amino-5-nitrobenzenesulfonic acid (200.00 g, 0.917 mol) was suspended in warm sulfolane (250 mL) and the suspension was heated to 80° C. Phosphorous oxychloride (126 mL, 1.375 mol) was added and resulting mixture was heated to 110-120° C. and stirred for 4 h. The resulting solution was cooled to 60° C. and added dropwise into concentrated aqueous ammonium hydroxide solution (800 mL, 11.9 mol) at <10° C. The flask was rinsed with warm sulfolane (50 mL) and the wash was added into the above reaction mixture. The resulting suspension was stirred at 25° C. for 1 h, heated to 95° C. and stirred for 1 hour. The mixture was cooled to 80° C. and the pH was adjusted to 6-8 with 3.0 M aqueous hydrochloric acid solution (˜600 mL) and allowed to cool to 25° C. The dark green suspension was filtered, and the wet filter cake was washed with water (300 mL) and dried at 60° C. overnight to give the crude product (140 g) as a green-yellow solid. The crude product was dissolved in 0.5 M aqueous sodium hydroxide solution (1.4 L, 0.7 mol). Charcoal (14 g) was added and the mixture was heated to reflux and stirred for 15 min. The mixture was filtered through Celite and washed with 0.5 M aqueous sodium hydroxide solution (100 mL). The pH of the filtrate was adjusted to 6-8 with concentrated aqueous hydrochloric acid solution (˜60 mL) and the yellow suspension was allowed to cool to 25° C. The mixture was filtered and the wet filter cake was washed with water (200 mL) and dried at 60° C. overnight to afford the desired product, 2-amino-5-nitrobenzenesulfonamide (130 g, 0.599 mol, 65%) as a bright yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Mg+2].[Cl-].[Cl-].[CH2:12]=[O:13]>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:12]=[O:13])=[C:4]([OH:8])[CH:3]=1
Reactant: Oc1cccc(F)c1
Reactant: C=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: O=Cc1ccc(F)cc1O
Temperature: 2.5 °C
Yield: 109 %

Procedure:
Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 3-fluorophenol (400 g, 3.57 mol, 1.00 equiv) in CH3CN (5 L), followed by the addition of MgCl2 (1018 g, 3.00 equiv) in several batches at 0° C. To this was added TEA (1443 g, 14.26 mol, 4.00 equiv) dropwise with stirring at 0-5° C., followed by paraformaldehyde (640 g, 6.00 equiv). The resulting solution was stirred at 80° C. for 3 h, cooled to 20° C., quenched by the addition of 5 L of 2N HCl and extracted with 3×3 L of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 545 g (crude) of 4-fluoro-2-hydroxybenzaldehyde as a yellow solid.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:18][N:17]=[N:16][C:15]=1[NH:27][NH2:28].ClC1N=NC=C(C2C=CC(Cl)=CC=2)C=1NN>C1COCC1>[Cl:13][C:14]1[C:15]2[N:16]([C:2](=[O:4])[NH:28][N:27]=2)[N:17]=[CH:18][C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NNc1nncc(-c2ccc(Cl)cc2)c1Cl
Agent: NNc1c(-c2ccc(Cl)cc2)cnnc1Cl
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirring solution of triphosgene (17.5 g, 59.0 mmol) in THF (150 mL) was cooled to 0° C. under argon and a mixture of 1-(4-chloro-5-(4-chlorophenyl)pyridazin-3-yl)hydrazine and 1-(3-chloro-5-(4-chlorophenyl)pyridazin-4-yl)hydrazine, as prepared in Example 361E, (3.0 g gross) was added over 3 min. The reaction mixture was then allowed to warm to RT gradually and then was stirred for 16 h. The solvent was removed under vacuum to reduce the reaction mixture to half its original volume, and the resulting suspension was cooled in an ice bath. Ice water (300 mL) was added, followed by stirring for 30 min. The product was collected by filtration and washed with 0.5 N aqueous HCl (20 mL×2), then H2O (20 mL×2). After drying under vacuum at room temperature for 16 h, the title compound, 8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (2.1 g) was obtained as a yellow solid. MS [M+H]+ 281; HPLC retention time=2.71 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([O-])=O>CO.[Pd]>[N:8]1([CH2:7][C:6]2[CH:5]=[C:4]([NH2:1])[C:16]([NH2:17])=[CH:15][CH:14]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CN2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 113.2 %

Procedure:
A mixture of 4-(3,4-dinitro-benzyl)-morpholine (550 mg) and 10% Pd/C (75 mg) in MeOH (10 ml) was shaken under a hydrogen atmosphere at ambient temperature for 4 hours, then filtered through a plug of Celite and reduced in vacuo to give 4-morpholin-4-ylmethyl-benzene-1,2-diamine (483 mg) as the major component of a mixture.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:22])[CH2:6][CH2:7]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
To 10 mL of a chloroform solution containing 500 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 246 mg of 2,3-dihydro-1,4-dioxino[2,3-c]pyridine-7-carbaldehyde, 100 mg of acetic acid was added, and stirred at room temperature for 2 hours. To the reaction mixture, 526 mg of sodium triacetoxyborohydride was added, and stirred for 18 hours. Aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 540 mg of 1-(2-(4-((2,3-dihydro-1,4-dioxino[2,3-c]pyridin-7-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxy-quinoxalin-2(1H)-one as a brown oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][C@H:2]12.[Br:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N:1]2[CH2:5][CH2:4][C@@H:3]3[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][C@H:2]23)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCN[C@H]2C1
Reactant: Brc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H]2CCN(c3ccc(Br)cc3)[C@H]2C1
Temperature: 140 °C

Procedure:
tert-Butyl(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (1, 1.5 g, 7.0 mmol), 1.4-dibromobenzene (2.8 g, 20.4 mmol), Pd2(dba)3 (275 mg, 0.3 mmol), BINAP (375 mg, 0.6 mmol) and sodium tert-butoxide (1.93 g, 20.0 mmol) were placed in glass microwave tubes and then purged three times with N2 gas, followed by the addition of toluene (45 mL). The mixture was heated to 140° C. for 15 minutes in a microwave reactor. The mixture was then cooled to room temperature, was filtered, and the crude mixture was purified via chromatography (SiO2, 0-25% ethyl acetate:hexanes) to provide the title compound. 1H NMR (300 MHz, CDCl3): δ=7.30 ppm (m, 2H), 7.39 (m, 2H), 4.11 (m, 1H), 3.57 (m, 3H), 3.31 (m, 3H), 2.99 (m, 1H), 2.15 (m, 1H), 1.92 (m, 1H), 1.43 (s, 9H). MS (ESI, M+1): 310.9.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[N:32]=[C:31]([C:33]([O:35][CH3:36])=[O:34])[CH:30]=[CH:29][CH:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.ClC1N=C(C(OC)=O)C=CC=1>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[N:32]=[C:31]([C:33]([O:35][CH3:36])=[O:34])[CH:30]=[CH:29][CH:28]=3)=[CH:25][N:26]=2)=[O:8])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cccc(-c2cnc(C(CCCCCCc3ccccc3)O[Si](C)(C)C(C)(C)C)o2)n1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: COC(=O)c1cccc(Cl)n1
Product: COC(=O)c1cccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)n1
Yield: 100 %

Procedure:
Methyl 6-(2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)picolinate. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (94 mg, 0.142 mmol) and methyl 6-chloropicolinate following General Procedure A. Flash chromatography (5-10% EtOAc/hexanes) yielded the title compound as a clear oil (72 mg, 100%): 1H NMR (CDCl3, 500 MHz) δ 8.12-8.10 (m, 1H), 7.99 (t, 1H, J=7.8 Hz), 7.90-7.89 (m, 1H), 7.86 (s, 1H), 7.35-7.32 (m, 2H), 7.25-7.22 (m, 3H), 4.94 (t, 1H, J=7.0 Hz), 4.10 (s, 3H), 2.67 (t, 2H, J=7.5 Hz), 2.04-1.96 (m, 2H), 1.74-1.67 (m, 2H), 1.55-1.39 (m, 6H), 0.97 (s, 9H), 0.17 (s, 3H), 0.07 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 166.5, 165.8, 150.3, 148.7, 148.2, 143.3, 138.4, 128.8, 128.6, 126.8, 126.0, 124.3, 122.5, 69.2, 53.4, 36.8, 36.3, 31.8, 29.6, 26.1, 26.1, 25.5, 14.0, −4.5, −4.7.
Reaction SMILES: [Na+:1].[Na+].[CH2:3]([NH:11][C:12]1[CH:13]=[C:14]([C:21]([O-:23])=[O:22])[C:15](=[CH:19][CH:20]=1)[C:16]([O-:18])=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Na+].[Na+].[CH2:26](NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]C.[Na+].[Na+].C(NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)CCCCCCCCC.[Na+].[Na+].C(NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)CCCCCCCCCC.[Na+].[Na+].[Na+].CC(NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)CCCCCCCCCC.[Na+].[Na+].C(NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)CCCCCCCCCCC.[Na+].[Na+].C(NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)CCCCCCCCCCCC.[Na+].[Na+].C(NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)CCCCCCCCCCCCC.[Na+].[Na+].C(NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)CCCCCCCCCCCCCC.[Na+].[Na+].CC(C)CCCCCCCCCCCCCNC1C=C(C([O-])=O)C(=CC=1)C([O-])=O.[Na][Na].[Na+].[Na+].C(NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)CCCCCCCCCCCCCCCCC.[Na+].[Na+].C(NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)CCCCCCCCCCCCCCCCCC>>[Na+:1].[Na+:1].[CH2:3]([NH:11][C:12]1[CH:13]=[C:14]([C:21]([O-:23])=[O:22])[C:15](=[CH:19][CH:20]=1)[C:16]([O-:18])=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCNc1ccc(C(=O)[O-])c(C(=O)[O-])c1
Reactant: CCCCCCCCCNc1ccc(C(=O)[O-])c(C(=O)[O-])c1
Agent: CC(C)CCCCCCCCCCCCCNc1ccc(C(=O)[O-])c(C(=O)[O-])c1
Agent: CCCCCCCCCCC(C)Nc1ccc(C(=O)[O-])c(C(=O)[O-])c1
Agent: CCCCCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])c(C(=O)[O-])c1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])c(C(=O)[O-])c1

Procedure:
Similarly, the 4-alkylaminophthalic acids described in Example 12 give, respectively, 4-octylaminophthalic acid disodium salt, 4-nonylaminophthalic acid disodium salt, 4-decylaminophthalic acid disodium salt, 4-undecylaminophthalic acid disodium salt, 4-(1-methylundecyl)aminophthalic acid disodium sodium salt, 4-dodecylaminophthalic acid disodium salt, 4-tridecylaminophthalic acid disodium salt, 4-tetradecylaminophthalic acid disodium salt, 4-pentadecylaminophthalic acid disodium salt, 4-(14-methylpentadecyl)aminophthalic acid disodium salt, 4-heptadecylaminophaltic acid disodium salt, 4-octadecylaminophthalic acid disodium salt, and 4-nonadecylaminophthalic acid disodium salt.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:17])[CH:15]=[CH2:16])=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]([C:23]1([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)=[O:22])[CH3:19]>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>[CH2:18]([O:20][C:21]([C:23]1([C:26]2[CH:31]=[CH:30][C:29]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:17])[CH:15]=[CH2:16])=[CH:4][CH:3]=3)=[CH:28][CH:27]=2)[CH2:24][CH2:25]1)=[O:22])[CH3:19]
Reactant: C=CC(O)c1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=CC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:23][CH2:22][C:18]2([CH2:21][O:20][CH2:19]2)[CH2:17][CH2:16]1)=O)(C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:19]1[C:18]2([CH2:22][CH2:23][NH:15][CH2:16][CH2:17]2)[CH2:21][O:20]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)COC2
Solvent: O=C(O)C(F)(F)F
Product: C1CC2(CCN1)COC2

Procedure:
Trifluoroacetic acid (125 mg, 1.1 mmol) was added at 0° C. to a solution of 2-oxa-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (U.S. Pat. No. 7,105,507 B2; 50 mg, 0.22 mmol) in dichloromethane, then after 1 h the reaction mixture was concentrated to afford the title compound (83 mg), which contained approximately one additional equivalent of trifluoroacetic acid. Colorless oil, 1H-NMR (300 MHz, DMSO-d6): 8.4 (br. s, 2H), 4.32 (s, 4H), 3.05-2.95 (m, 4H), 1.95-1.9 (m, 4H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[CH3:13][N:14]=[C:15]=S>>[CH3:13][NH:14][C:15]1[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[N:12]=1
Reactant: CN=C=S
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Product: CNc1nc2cc([N+](=O)[O-])ccc2n1C
Yield: 53.3 %

Procedure:
N1-methyl-4-nitro-benzene-1,2-diamine (2.0 g, 12.0 mmol) and methyl isothiocyanate (0.90 ml, 13.2 mmol) were coupled using the procedure of example one part B to give the title compound as a yellow solid (1.32 g, 53%). 1H NMR (300 MHz, d6-DMSO) δ 7.98 (d, J=2.1 Hz, 1H), 7.90 (dd, J=8.7 and 2.4 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.15 (m, 1H), 3.55 (d, 3H), 2.95 (d, J=4.5 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][C:5]=1[O:26][CH3:27])([O-])=O.O.O.Cl[Sn]Cl.C(O)C.O1CCCC1>C(Cl)Cl>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][C:5]=1[O:26][CH3:27]
Reactant: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 0.91 g of 10,11-dihydro-10-(4-nitro-3-methoxybenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 4.51 g of SnCl2.2H2O, 6 ml of ethyl alcohol, 6 ml of tetrahydrofuran and 16 ml of methylene chloride is stirred at 50° C. for 2 hours. The solvents are evaporated in vacuo and the residue dissolved in 80 ml of ethyl acetate. The solution is treated with 50 ml of 1N NaOH with stirring for 30 minutes. The resulting suspension is filtered through diatomaceous earth. The pad is washed with ethyl acetate (3×15 ml). The combined ethyl acetate solutions are washed with brine, dried (Na2SO4), filtered through hydrous magnesium silicate and evaporated in vacuo to 0.99 g of residue which is stirred with ether-hexanes to give 0.90 g of cream colored solid. MS(CI):334(M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][C:5]=1[O:26][CH3:27])([O-])=O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][C:5]=1[O:26][CH3:27]
Reactant: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Yield: 67.3 %

Procedure:
A mixture of 3.24 g of 10,11-dihydro-10-(4-nitro-3-methoxybenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.35 g of 10% Pd/c and 0.60 g of anhydrous hydrazine in 100 ml of absolute ethyl alcohol and heated on a steam bath for 1 hour. The hot reaction mixture is filtered through diatomaceous earth and the filtrate evaporated in vacuo to a residue which is partitioned between methylene chloride and water. The organic layer is dried with Na2SO4 and passed through a short pad of hydrous magnesium silicate. Hexane is added to the filtrate while heating on a steam bath to give 2 g of crystals, m.p. 184°-185° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:19])[CH:15]([CH3:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([C:25]1([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23]([C:25]1([C:28]2[CH:33]=[CH:32][C:31]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:19])[CH:15]([CH3:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=3)=[CH:30][CH:29]=2)[CH2:26][CH2:27]1)=[O:24])[CH3:21]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: C=CC(C)C(O)c1c(C)noc1-c1ccc(Br)cc1
Product: C=CC(C)C(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-methyl-but-3-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)NCCC2
Yield: 101.2 %

Procedure:
A solution of 7-nitro-1,2,3,4-tetrahydroquinoline (396 mg, 0.0022 mol) in 4 mL of ethyl acetate was hydrogenated under an atmosphere of hydrogen with PdC 10% (40 mg) at rt for 2 h. Filtration over celite afforded 330 mg (100%) of 7-amino-1,2,3,4-tetrahydroquinoline. Data for 7-amino-1,2,3,4-tetrahydroquinoline: 1H NMR (400 MHz, CDCl3) 6.72 (d, J=7.9, 1H), 6.00 (dd, J=7.9, 2.3, 1H), 5.84 (d, J=2.3, 1H), 3.67 (bs, 1H), 3.42 (bs, 2H), 3.24 (t, J=5.0, 2H), 2.65 (t, J=6.4, 2H), 1.91 (quintet, J=6.0 Hz. 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[CH2:2].[F:20][C:21]1[C:31](I)=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:23]([OH:33])[CH:22]=1.CN.CN(C)C(=O)C>C(Cl)(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:20][C:21]1[C:31]([CH:2]=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([S:9]([NH:12][C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=3)(=[O:10])=[O:11])=[CH:7][CH:8]=2)=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:23]([OH:33])[CH:22]=1
Reactant: CCOC(=O)c1cc(I)c(F)cc1O
Reactant: C=Cc1ccc(S(=O)(=O)Nc2ncccc2C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(C=Cc2ccc(S(=O)(=O)Nc3ncccc3C)cc2)c(F)cc1O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
4-Ethenyl-N-(3-methyl-2-pyridinyl)benzenesulfonamide (2.7 g, 10 mmol), ethyl 4-fluoro-2-hydroxy-5-iodobenzoate (3.6 g, 80%, 10 mmol), methylamine (5 ml) and N,N-dimethylacetamide (5 ml) were mixed and heated to 50° C. Palladium acetate (40 mg) was added and the solution kept at 50° C. for 18 h. The solution was poured into water and the precipitate dissolved in chloroform. The solution was dried, applied on top of a short silica gel column and eluted with 30% isobutylmethylketone in toluene. The pure fractions were collected and evaporated to dryness. After trituration with acetonitril the product crystallized. Yield 1.1 g.
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2)([O-])=O>C(O)C.[Fe]>[NH2:5][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cccc2[nH]ccc12
Yield: 99.9 %

Procedure:
Iron powder (1.20 g, 21.58 mmol) and acetic acid (2.47 mL, 43.19 mmol) are added to a solution of 4-nitroindole (1.0 g, 6.17 mmol) in ethanol (20 mL). The resulting suspension is heated to reflux for 14 hours. The ethanol is removed by rotary evaporation and the residue is partitioned between water and ethyl acetate. The ethyl acetate layer is dried over magnesium sulfate, filtered, and the solvents removed by rotary evaporation. The crude residue is purified via silica gel column chromatography using 1% methanol/methylene chloride as the eluent. The appropriate fractions are combined and the solvents removed by rotary evaporation to yield 0.815 g of 4-aminoindole as an orange solid (82% yield).