Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[C:6]3[C:7](=[CH:13][CH2:14][NH2:15])[CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][C:4]=2[N:3]=[CH:2]1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(=O)([O-])O.[Na+]>O1CCCC1>[O:1]1[C:5]2[C:6]3[C:7](=[CH:13][CH2:14][NH:15][C:23](=[O:25])[CH3:24])[CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][C:4]=2[N:3]=[CH:2]1
Reactant: CC(=O)OC(C)=O
Reactant: NCC=C1CCc2ccc3ncoc3c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCC=C1CCc2ccc3ncoc3c21
Reaction time: 0.25 h
Yield: 53 %

Procedure:
2-(6,7-Dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethanamine (30.0 mg, 0.148 mmol) was dissolved in tetrahydrofuran (1 mL), triethylamine (31.0 μL, 0.222 mmol) and acetic anhydride (16.8 μL, 0.178 mmol) were added under ice-cooling, and the mixture was stirred for 15 min. To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→95/5) to give the title compound (19.0 mg, yield 53%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:7])[CH:5]=[O:6].O=C1NC2[C:11](=[N:12][C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][CH:15]=2)[N:10]1[CH2:24][C:25]([N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])=[O:26].CI>C(Cl)(Cl)Cl.O>[CH3:3][N:4]1[C:7]2[C:11](=[N:12][C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][CH:15]=2)[N:10]([CH2:24][C:25]([N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])=[O:26])[C:5]1=[O:6]
Reactant: CCCN(CCC)C(=O)Cn1c(=O)[nH]c2cnc(-c3ccccc3)nc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCN(CCC)C(=O)Cn1c(=O)n(C)c2cnc(-c3ccccc3)nc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of about 60% sodium hydride (oily) (0.8 g) and dimethylformamide (50 ml) is added 7,8-dihydro-8-oxo-2-phenyl-N,N-dipropyl-9H-purin-9-acetamide (6 g) obtained in Example 79 in portions at 0-5° C., and the mixture is stirred at 0° C. for one hour. To the mixture is added dropwise methyl iodide (2.9 g) at the same temperature. After the addition, the mixture is stirred at room temperature for two hours. To the reaction mixture are added water and chloroform, and the chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from ethanol to give the desired compound (6 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][C:31]([OH:35])=[CH:32][CH:33]=2)[N:28]([CH3:36])[C:27]=1[CH3:37])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+]>>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][C:31]([O:35][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=5)[S:10][C:3]=34)=[CH:32][CH:33]=2)[N:28]([CH3:36])[C:27]=1[CH3:37])=[O:25]
Reactant: Cc1c(C(=O)Nc2ccccn2)c2ccc(O)cc2n1C
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1c(C(=O)Nc2ccccn2)c2ccc(Oc3ccnc4cc(-c5nccn5C)sc34)cc2n1C

Procedure:
This material was prepared by the reaction of 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid pyridin-2-ylamide 69b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, DMSO-d6) δ8.43 (1H, d, J=5.5 Hz), 8.33 (1H, s), 8.20 (1H, d, J=3.8 Hz), 7.75-7.95 (3H, m), 7.61 (1H, s), 7.40 (1H, s), 7.11 (2H, m), 7.03 (1H, s), 6.60 (1H, d, J=5.5 Hz), 4.05 (3H, s), 3.73 (3H, s), 2.68 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 495, found 495.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].C[O:17][CH:18]1[CH:22]([CH:23]=O)[CH2:21][CH:20](OC)O1>C(O)(=O)C>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([N:6]2[CH:20]=[CH:21][C:22]([CH:18]=[O:17])=[CH:23]2)[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: COC1CC(C=O)C(OC)O1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: O=Cc1ccn(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)aniline (3.58 g) and 2,5-dimethoxy-3-tetrahydrofurancarbaldehyde (2.50 g) in acetic acid (16 mL) was stirred at 90° C. for 30 min. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and saturated sodium hydrogencarbonate solution. The ethyl acetate layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 70:30) to give the title compound (2.44 g, yield 51%) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CN(C)C=O>[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][C:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:34]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(O)COc1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(COc1ccccn1)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.6 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 1, (3), 2-(pyridin-2-yloxy)acetic acid (23 mg, 0.15 mmol), HATU (23 mg, 0.15 mmol), triethylamine (0.04 mL), and dry dimethylformamide (1 mL) were mixed, and the mixture was stirred at room temperature for 2 hours. This reaction mixture was added with water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/chloroform=1/50) to give the title compound (22 mg, yield 49%) as pale yellow crystals.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].NC1C2C(=CC=CC=2)C=CC=1.ClC(Cl)(Cl)C(O)O.Cl.[NH2:31][OH:32].S([O-])([O-])(=O)=O.[Na+].[Na+]>>[CH:8]1[CH:7]=[CH:6][C:11]([NH:1][C:2](/[CH:4]=[N:31]/[OH:32])=[O:3])=[CH:10][CH:9]=1
Reactant: NO
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cl
Agent: Nc1cccc2ccccc12
Agent: O=S(=O)([O-])[O-]
Product: O=C(/C=N/O)Nc1ccccc1
Yield: 34 %

Procedure:
The procedure described above for the synthesis of intermediate 3 was followed, reacting 1-aminonaphthalene (10.0 g, 69.8 mmol) with chloral hydrate (13.9 g, 83.8 mmol) and hydroxylamine hydrochloride (17.5 g, 0.251 mol) in the presence of sodium sulfate (99 g, 0.70 mol). Isonitrosoacetanilide was obtained as a brownish-black solid (7.09 g, 47% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:9])=[C:4](C)[CH:5]=[CH:6][CH:7]=1.[C:10](OCC)(=O)C>>[N:9]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH:10]=1
Reactant: CCOC(C)=O
Reactant: Cc1cccc(N)c1N
Product: c1ccc2[nH]cnc2c1

Procedure:
Whne diaminotoluene was treated with 4-chlorophenoxynitrile there was no precipitate observed immediately. The reaction mixture was condensed under vacuum. The crude brownish solid was dissolved in ethyl acetate. The resulting solution was washed with water, then brine, and then dried over sodium sulfate. The solvents were then removed in vacuo to produce brown crystals with a good yield.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:17][C:18](=[O:20])[CH3:19])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[S:7][CH:8]=1)(=O)[CH3:2].[NH:21]([C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([N+:34]([O-:36])=[O:35])[CH:26]=1)=[O:24])[NH2:22]>>[C:18]([O:17][C:5]1[C:4]([C:1](=[N:22][NH:21][C:23]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([N+:34]([O-:36])=[O:35])[CH:26]=2)=[O:24])[CH3:2])=[CH:8][S:7][C:6]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)(=[O:20])[CH3:19]
Reactant: NNC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: CC(=O)Oc1c(C(C)=O)csc1-c1ccc(Cl)c(Cl)c1
Product: CC(=O)Oc1c(C(C)=NNC(=O)c2ccc(C(=O)O)c([N+](=O)[O-])c2)csc1-c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from acetic acid 4-acetyl-2-(3,4-dichlorophenyl)thiophen-3-yl ester (39.5 mg, 0.12 mmol) and 4-hydrazinocarbonyl-2-nitrobenzoic acid (40.5 mg, 0.18 mmol) following the procedure described in the synthetic example 185.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]([C:15]([C:18]#[N:19])([CH3:17])[CH3:16])[CH:12]=[C:11]([F:20])[C:3]=1[C:4]([NH:6][C:7]([CH3:10])(C)C)=[O:5].C(=O)([O-])[O-].[K+].[K+].C(O/C=C/B1OC(C)(C)C(C)(C)O1)C.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>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]>[F:20][C:11]1[CH:12]=[C:13]([C:15]([CH3:16])([CH3:17])[C:18]#[N:19])[CH:14]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][CH:7]=[CH:10]2
Reactant: CC(C)(C)NC(=O)c1c(F)cc(C(C)(C)C#N)cc1Br
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Product: CC(C)(C#N)c1cc(F)c2c(=O)[nH]ccc2c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
A 500 mL round-bottomed flask was charged with 2-bromo-N-tert-butyl-4-(2-cyanopropan-2-yl)-6-fluorobenzamide (34.5 g, 101 mmol, 1 equiv.) and potassium carbonate (27.9 g, 202 mmol, 2 equiv.) and the flask was subsequently purged with nitrogen (3 times). 1,4-dioxane (242 ml) and water (34.5 ml) were added. The E-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (28.0 g, 142 mmol, 1.4 equiv.) was then added by syringe. The reaction mixture was heated to 40° C. To the mixture was added bis(dibenzylideneacetone)palladium (2.33 g, 4.04 mmol, 0.04 equiv.) and tricyclohexylphosphine (2.27 g, 8.09 mmol, 0.08 equiv.) and the resulting mixture was heated with stirring at 90° C. (inner temperature)/100° C. (bath) for 2 h until reaction was complete. The reaction mixture was cooled to ambient temperature and quenched with 20% NaHSO3 solution (150 mL) followed by stirring for 2 hr. The mixture was extracted with EtOAc (2 times), dried over MgSO4, and concentrated under reduced pressure. The resultant product was dissolved with TFA (138 ml) in a 350 mL pressured bottle and heated to 100° C. (bath temp.) for 3 hr. The reaction mixture was transferred to a round-bottomed flask with toluene, and the TFA was removed under reduced pressure, then basified with 20% K2CO3 solution. The reaction mixture was extracted with EtOAc and then with DCM. Crystallization from methyl-tert-butylether afforded 2-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-6-yl)-2-methylpropanenitrile (16.2 g, 69.6% yield) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.74 (s, 6 H) 6.60 (dd, J=6.99, 1.70 Hz, 1 H) 7.16-7.28 (m, 1 H) 7.36 (dd, J=13.03, 1.70 Hz, 1 H) 7.61 (d, J=1.89 Hz, 1 H) 11.31 (br. s., 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[OH:10].[H-].[Na+].[CH2:13]([O:15][C:16](=[O:27])[C:17]1[CH:22]=[C:21](Cl)[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])[CH3:14]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[O:10][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH:22]=1)[C:16]([O:15][CH2:13][CH3:14])=[O:27]
Reactant: CCOC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(Oc2cc(Cl)c(Cl)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 38.8 %

Procedure:
2,4,5-Trichlorophenol (20 g) in dry dimethylacetamide (40 ml) was treated with sodium hydride (5.28 g of 50% dispersion in oil) in portions and the resulting mixture heated to 120° C. Ethyl-5-chloro-2-nitrobenzoate (16.5 g) was added in solution in dry dimethylacetamide (60 ml) and the mixture heated at 160° C. for ten hours. The solvent was removed and the residue washed with water and extracted with ether. The ether solution was extracted with ether. The ether solution was evaporated. The remaining oil solidified and was recrystallised from ethanol to give ethyl 5(2,4,5-trichlorophenoxy)-2-nitrobenzoate (10.9 g) with a melting point of 99°-102° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].[Br:19][CH2:20][CH2:21]Br>CC#N>[Br:19][CH2:20][CH2:21][O:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc([N+](=O)[O-])cc1OCCBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.4 %

Procedure:
To a mixture of 2-hydroxy-4-nitro-benzonitrile (2 g, 12.19 mmol) and K2CO3 (3.36 g, 24.39 mmol) in MeCN (20 mL) was added 1,2-dibromoethane (3.4 g, 18.29 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h while monitoring by TLC. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate (100 mL) and washed with brine (2×25 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated to give 2-(2-bromoethoxy)-4-nitrobenzonitrile (1.6 g, 49%) as a light red solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.94-7.92 (1H, m), 7.82-7.78 (2H, m), 4.52 (2H, t, J=6.4 Hz), 3.73 (2H, t, J=6.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[C:3]=1[CH3:22]>[Pt]=O.C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][C:12]2[N:13]=[C:14]3[C:19]([CH2:18][CH2:17][CH2:16][NH:15]3)=[CH:20][CH:21]=2)[C:3]=1[CH3:22]
Reactant: Cc1c(Cl)ncnc1OCCCc1ccc2cccnc2n1
Agent: O=[Pt]
Solvent: CCO
Product: Cc1c(Cl)ncnc1OCCCc1ccc2c(n1)NCCC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.7 %

Procedure:
A sufficient quantity of ethanol to solubilize the product, and 15 mg of platinum oxide are added to 300 mg (0.953 mmoles) of 2-[3-(6-chloro-5-methyl -pyrimidin-4-yloxy)-propyl]-[1,8]naphthyridine. The reaction mixture is then purged under vacuum and surmounted on a balloon flask containing hydrogen. The reaction medium is left under stirring and at ambient temperature for 6 hours then overnight. The reaction mixture is then filtered on Clarcel and concentrated to dryness under reduced pressure (2 kPa). Then 300 mg of expected product is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])=[O:8])=[CH:5][CH:4]=1)#[N:2].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:60][O:61][C:62](=[O:70])[CH2:63][CH:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>C(Cl)Cl>[CH3:60][O:61][C:62](=[O:70])[CH2:63][CH:64]1[CH2:65][CH2:66][N:67]([C:12](=[O:13])[C:11]([CH3:15])([CH3:16])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:25][CH:24]=2)[CH2:68][CH2:69]1
Reactant: COC(=O)CC1CCNCC1
Reactant: CC(C)(C(=O)O)C(NC(=O)c1ccc(C#N)cc1)c1cccc(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC1CCN(C(=O)C(C)(C)C(NC(=O)c2ccc(C#N)cc2)c2cccc(Cl)c2)CC1
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
N-4-Cyanobenzoyl-β-m-chlorophenyl-α,α-dimethyl-β-alanine (300 mg, 0.84 mmol) was dissolved in methylene chloride (30 ml). To the resulting solution, BOP reagent (409 mg, 0.92 mmol) and triethylamine (1 ml) were added under cooling with ice and the mixture was stirred for 30 minutes. To the reaction mixture was added 4-piperidineacetic acid methyl ester (572 mg, 3.36 mmol) and the resulting mixture was stirred overnight. After the solvent was distilled off, the residue was applied to a silica gel column (2.2×20 cm) and eluted with a mixed solution (hexane:ethyl acetate=3:1). The desired fractions were collected and the solvents were distilled off to yield an oil of N-4-cyanobenzoyl-β-m-chlorophenyl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid methyl ester (270 mg, 65.0%).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([C:23]#[C:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]>C(O)C.[Ni]>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(C#Cc4ccc(Cl)cc4)cc3c12
Agent: [Ni]
Solvent: CCO
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(CCc4ccc(Cl)cc4)cc3c12
Yield: 58.5 %

Procedure:
100 mg of 6-(4-chlorophenylethinyl)-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester is hydrogenated for 1 hour in 20 ml of ethanol with 1 spatula-tip full of Raney nickel (decanted twice with ethanol) at room temperature and hydrogen standard pressure. After filtering off from the catalyst on silica gel it is concentrated by evaporation and the residue is recrystallized from ethyl acetate/hexane. It yields 59 mg (59% of theory) of 6-(4-chlorophenylethyl)-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester, melting point 182°-184° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:13]2[CH:18]=[C:17]([N+:19]([O-])=O)[C:16]([O:22][CH3:23])=[C:15]([O:24][CH3:25])[CH:14]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C:13]2[CH:14]=[C:15]([O:24][CH3:25])[C:16]([O:22][CH3:23])=[C:17]([NH2:19])[CH:18]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc(C(NC(C)c2ccc(F)c(F)c2)c2ccc(F)cc2)cc([N+](=O)[O-])c1OC
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1cc(C(NC(C)c2ccc(F)c(F)c2)c2ccc(F)cc2)cc(N)c1OC

Procedure:
Following a similar reaction, separation and purification procedure to that described in Example (59b), 3.42 g of N-[1-(3,4-difluorophenyl)ethyl]-N-[(4-fluorophenyl)-(3,4-dimethoxy-5-nitrophenyl)methyl]amine [prepared as described in step (a) above], 3.65 g of nickel chloride hexahydrate and 1.17 g of sodium borohydride were reacted, to obtain 1.10 g of isomer A and 1.39 g of isomer B of the title compound as pale yellow oils, respectively.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10]Cl.Cl.[F:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][N:17]1[CH2:18][CH2:19][CH:14]([F:13])[CH2:15][CH2:16]1
Reactant: ClCCOc1ccccc1Br
Reactant: FC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: FC1CCN(CCOc2ccccc2Br)CC1
Temperature: 80 °C
Yield: 33.2 %

Procedure:
A mixture of 1-bromo-2-(2-chloroethoxy)benzene (2.35 g), 4-fluoropiperidine hydrochloride (1.54 g), potassium carbonate (4.06 g) and potassium iodide (0.83 g) in dimethylformamide (20 ml) was heated at 80° C. for 18 h. After evaporation, the residue was partitioned between ethyl acetate and water. The solvent phase was washed (brine), dried and evaporated to give an oil (1.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Reactant: NC1CC1
Solvent: ClCCl
Product: O=S(=O)(NC1CC1)c1ccc(Br)cc1F
Yield: 44.2 %

Procedure:
According to general procedure C, 4-Bromo-2-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and cyclopropylamine (0.25 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-cyclopropyl-2-fluorobenzenesulfonamide (190 mg, 44%) was provided after purification. MS (ESI) m/z 294. HPLC purity 98.6% at 210-370 nm, 10.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: O[C:2]([CH3:12])([CH3:11])[C:3](C1C=CC=CC=1)=[O:4].O[CH2:14][CH:15]([CH2:17][OH:18])[OH:16]>>[C:3]([O:18][CH2:17][CH:15]1[O:16][CH2:14]1)(=[O:4])[C:2]([CH3:12])=[CH2:11]
Reactant: OCC(O)CO
Reactant: CC(C)(O)C(=O)c1ccccc1
Product: C=C(C)C(=O)OCC1CO1
Reaction time: 8 h

Procedure:
After sitting overnight a 50 g portion of each of the 15,000 and 10,000 mw functionalized materials were formulated with 49 g of glycerin and 1 g of 2-hydroxy-2-methyl-1-phenyl-propan-1-one, a photoinitiator available from Ciba-Giegy Corporation, Hawthorne, N.Y. under the tradename Darocur® 1173.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[CH:3][CH:2]=1.C[OH:15]>N1C=CC=CC=1>[N:4]1[CH:3]=[CH:2][CH:1]=[C:13]2[C:12](=[O:15])[C:11]3[C:6]([C:5]=12)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: c1ccc2c(c1)Cc1cccnc1-2
Reactant: CO
Solvent: c1ccncc1
Product: O=C1c2ccccc2-c2ncccc21

Procedure:
See general oxidation method of Sprinzak, J. Am. Chem. Soc., 80 (1958) 5449. 4-Azafluorene (5.0 g, 30 mmol) was dissolved in 50 mL anhydrous pyridine containing in solution 2 mL Triton B solution (prepared by evaporating 5 mL of 40% Triton B in methanol (Aldrich Chemical, Inc.) and 5 mL pyridine with heat and reduced pressure followed by q.s. to 10 mL with pyridine). Then air was continuously bubbled through the solution with stirring. An addition of 2 mL Triton B solution was made twice more at two-hour intervals. After six hours the reaction mixture was evaporated to dryness. The residue was triturated in 30 mL water and extracted four times with ethyl acetate (total volume 200 mL). The combined ethyl acetate extracts were dried over anhydrous sodium sulfate. After filtration and evaporation, the residue was chromatographed (silica gel and chloroform) to yield after evaporation of the solvent 4.5 g (83%) of (28). m.p. 132°-136° C. (reported 142° C.).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[N+:14]([O-:16])=[O:15]>O>[OH:2][CH2:1][CH2:3][NH:4][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[N+:14]([O-:16])=[O:15]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCCO
Solvent: O
Product: N#Cc1ccc(NCCO)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
Monoethanolamine (38 ml; 0.62 mol) was added to a suspension of 4-chloro-3-nitrobenzonitrile (51.6 g; 0.28 mol) in 270 ml water. The reaction mixture was refluxed for one hour at 100°-110° C. (oil bath). After cooling to room temperature, the orange precipitate was filtered, washed with water and air-dried to give 55.8 g 4-(2-hydroxyethylamino)-3-nitrobenzonitrile (m.p.=132°-134° C.). The yield was about 95%, with the overall yield for the reaction sequence, illustrated below, being about 81%. ##STR6##