Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[C@@H:10]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:11][CH2:12][C:13](=O)[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C[Si]([N:69]=[N+:70]=[N-:71])(C)C.N([O-])=O.[Na+]>C(#N)C.O>[CH2:1]([O:8][C:9](=[O:31])[C@@H:10]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:11][CH2:12][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:69][NH:70][N:71]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)NCc1ccccc1)C(=O)OCc1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCC1=NNNN1Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 0.83 g (S)-4-benzylcarbamoyl-2-tert-butoxycarbonylamino-butyric acid benzyl ester and 1.28 g triphenylphosphine in 16 ml acetonitrile were added dropwise at 0° C. 1.00 ml diisopropylazodicarboxylate and after 2 minutes 0.67 ml trimethylsilylazide over a period of 10 minutes. After 30 minutes the mixture was allowed to warm to RT and stirred for 12 h. The mixture was cooled to 0° C. and 0.67 ml aqueous sodium nitrite (2.9 M) were added, after 30 minutes a solution of 1.07 g ceric ammonium nitrate in 10 ml water was added and stirred for another 20 minutes. After this time the mixture was poured into ice and extracted twice with dichloromethane.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[C:12]([CH2:19][CH2:20][CH2:21][CH:22]=[CH:23][C:24]([OH:26])=[O:25])=[N:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[C:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[N:11]2)=[CH:6][CH:5]=1
Reactant: O=C(O)C=CCCCc1nn(-c2ccc([N+](=O)[O-])cc2)c2c1CCCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(-n2nc(CCCCCC(=O)O)c3c2CCCC3)cc1

Procedure:
A solution of 6-[4,5,6,7-tetrahydro-1-(4-nitrophenyl)-1H-inda-zol-3-yl]hexenoic acid n acetic acid (75 ml) was treated with 10% palladium/C (0.80 g) and reduced at 40 psi hydrogen pressure for 2 hours. The catalyst was filtered and the filtrate was evaporated to yield crude 1-[4-(amino)phenyl]-4,5,6,7-tetrahydro-1H-indazole-3-hexanoic acid. Acylation with acetic anhydride (5 ml) and pyridine (10 ml) gave crude title compound (0.45 g). An analytical sample (m.p. 175° C.) was obtained from methanol-ether solution.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]2[NH:8][NH:9][C:10](=[O:12])[CH:11]=2)=[CH:3][CH:2]=1.[Mg].[CH3:20]I.Cl>C1COCC1>[C:1]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH3:20])[CH2:11][C:10](=[O:12])[NH:9][NH:8]2)=[CH:3][CH:2]=1
Reactant: CI
Reactant: O=c1cc(-c2ccc(-c3ccccc3)cc2)[nH][nH]1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(c2ccc(-c3ccccc3)cc2)CC(=O)NN1

Procedure:
A solution of 23.6 g of 3-(4-biphenylyl)-pyrazolin-5-one [obtainable from 3-(4-biphenylyl)-3-oxopropionic acid ethyl ester and hydrazine] in 400 ml of THF is added dropwise, while stirring and cooling, to a Grignard solution prepared from 4.8 g of magnesium and 28.4 g of methyl iodide in 800 ml of absolute THF. After stirring for 2 hours at 10°-25°, the mixture is decomposed with ice and dilute hydrochloric acid and worked up in the usual manner to give 3-(4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 191°-192°.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][NH:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[F:1][C:2]([F:14])([F:15])[CH2:3][NH:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(CNCC(F)(F)F)cc1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NCc1ccc(CNCC(F)(F)F)cc1
Yield: 49 %

Procedure:
Dissolve 4-[(2,2,2-trifluoroethylamino)-methyl]-benzonitrile (633 mg, 2.955 mmol) in methanol (22 mL). Add cobalt(II) chloride hexahydrate (1.41 g, 5.91 mmol) and stir for 20 min. Carefully add sodium borohydride (1.12 g, 29.55 mmol) in small batches and stir the mixture overnight. Quench the mixture with water and filter through celite, washing filtercake with chloroform:methanol:concentrated NH4OH (80:18:2). Concentrate the filtrate in vacuo, and partition the residue between water and chloroform. Extract the aqueous phase three times with chloroform iso-propanol (3:1). Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (40 g, pre-packed cartridge) eluting with DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) (1:0 over 5 min, 19:1 over 5 min, 9:1 over 5 min, 85:15 over 5 min, 4:1; 50 mL/min) to obtain the title compound (316 mg, 49%). MS (ES+) m/z: 219 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].N1C=CN=C1.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21].O>CN(C)C=O>[Si:24]([O:1][CH2:2][C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CON(C)C(=O)c1ccccc1CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1ccccc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of phthalide (26.8 g) in methylene chloride (600 ml) were successively added N,O-dimethylhydroxylamine hydrochloride (58.5 g) and aluminum chloride (40.0 g) under ice-cooling, and triethylamine (139 ml) was added dropwise over 40 min. The mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into diluted hydrochloric acid, and the organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-hydroxymethyl-N-methoxy-N-methylbenzamide. The obtained 2-hydroxymethyl-N-methoxy-N-methylbenzamide was dissolved in N,N-dimethylformamide (300 ml), and imidazole (9.53 g) and tert-butyldimethylchlorosilane (21.1 g) were added. The mixture was stirred at room temperature for 3.5 hr and the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give the title compound (42.0 g).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]1[CH:16]([C:17]#[N:18])[NH:15][C:14]1=[O:19].N1C=CC=CC=1.[C:26]1([CH2:32][C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.O>[C:17]([C@H:16]1[NH:15][C:14](=[O:19])[C@H:13]1[NH:12][C:33](=[O:34])[CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[N:18]
Reactant: N#CC1NC(=O)[C@H]1N
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#C[C@H]1NC(=O)[C@H]1NC(=O)Cc1ccccc1
Temperature: 25 °C

Procedure:
In 100 ml of methylene chloride were dissolved under ice-cooling 5 g of p-toluenesulfonate of (3S, 4RS)-3-amino-4-cyano-2-azetidinone and 4.2 g of pyridine. To the solution was added 3 g of phenylacetyl chloride. The mixture was stirred at room temperature (about 25° C.) for ten minutes, which was shaken with water. The organic layer was separated and dried on anhydrous magnesium sulfate, then concentrated under reduced pressure. The concentrate was purified on a silicagel column chromatography [ethyl acetate:n-hexane (2:1)] to yield 1.16 g of (3S, 4S)-4-cyano-3-phenylacetamido-2-azetidinone (A) and subsequently 0.84 g of a corresponding (3S, 4R)-derivative (B).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:14]1([NH2:21])[CH2:19][CH2:18][CH2:17][CH:16]([NH2:20])[CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:20][CH:16]1[CH2:17][CH2:18][CH2:19][CH:14]([NH:21][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=3)[NH:8][CH:9]=2)=[O:13])[CH2:15]1
Reactant: O=C(O)c1c[nH]c2ncc(Br)nc12
Reactant: NC1CCCC(N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC1CCCC(NC(=O)c2c[nH]c3ncc(Br)nc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.2 g, 0.83 mmol), cyclohexane-1,3-diamine (0.473 g, 4.15 mmol), HATU (0.475 g, 1.25 mmol), DIPEA (0.322 g, 2.5 mmol) in 15 mL of DMF were stirred at room temperature overnight. The solvent was removed under reduced pressure at 70° C. to give N-(3-aminocyclohexyl)-2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide as a crude which was used to the next step without further purification. MS: (M+H)+=338.1.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][N:4]=1.[CH3:13][OH:14]>>[CH3:13][O:14][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][N:4]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: CO
Agent: [Na]
Product: COc1cc(C)c([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a stirred solution of sodium (2.30 g, 100 mmol, 3.8 eq) in absolute methanol (75 ml) at 0° C., a solution of 2-chloro-4-methyl-5-nitropyridine (4.50 g, 26.07 mmol) in absolute methanol (15 ml) was added dropwise rapidly. The resulting dark colored solution was stirred at room temperature for 30 minutes, and then it was concentrted to a solid via evaporation under reduced pressure. This solid was placed in water (25 ml), the pH of which was ad]usted to 6 with concentrated HCl, and this aqueous mixture was extracted with ethyl acetate (2×25 ml). These extracts were combined, dried (MgSO4), and evaporated under reduced pressure to yield 2-methoxy-4-methyl-5-nitropyridine (4.30 g, 25.57 mmol, 98%) as an orange solid: mp, 70°-72° C.; 1H NMR (DMSO-d6) δ 8.94 (s, 1H), 6.97 (s, 1H), 3.99 (s, 3H), 2.58 (s, 3H); LRMS (m/z relative intensity) 168 (M+, 98), 167 (100), 151 (34), 138 (24), 80 (17).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Br:32])[C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=1)[C:5]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:6].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([NH:7][C:5](=[O:6])[C:4]2[CH:3]=[C:2]([Br:1])[C:22]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=3)=[C:21]([Br:32])[CH:20]=2)(=[O:9])=[O:10])=[CH:12][CH:13]=1
Reactant: O=C(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)NC(=O)c2cc(Br)c(OCc3cccc(Br)c3)c(Br)c2)cc1
Temperature: 70 °C
Yield: 19.4 %

Procedure:
To a solution of N-[3,5-dibromo-4-(3-bromobenzyloxy)benzoyl]-4-nitrobenzenesulphonamide (0.25 mmol), prepared as described in Example 33, in ethanol (95%, 25 mL), sodium dithionite (1.26 mmol) was added and the reaction mixture stirred over night at 70° C. The reaction mixture was allowed to reach room temperature and then evaporated in vacuo. The residue was diluted with ethyl acetate and washed with an aqueous solution of sodium hydrogencarbonate (saturated). The organic phase was dried over magnesium sulphate and concentrated in vacuo. The residue was purified on column (silica gel, chloroform/methanol 17:3) and further purified by semi-preparative HPLC (column and eluents as described for Examples 27, 28 an 30) to give 30 mg (20%) of 4-amino-N-[3,5-dibromo-4-(3-bromobenzyloxy)-benzoyl]benzenesulphonamide.
Reaction SMILES: C1C2C(COC([NH:18][C:19]3([C:24]([N:26]([CH2:55][CH:56]([CH3:58])[CH3:57])[NH:27][C:28](=[O:54])[C@@H:29]([C@@H:34]([C:44](=[O:53])[NH:45][O:46][CH:47]4[CH2:52][CH2:51][CH2:50][CH2:49][O:48]4)[CH2:35]/[CH:36]=[CH:37]/[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1>ClCCl.N1CCCCC1>[NH2:18][C:19]1([C:24]([N:26]([CH2:55][CH:56]([CH3:58])[CH3:57])[NH:27][C:28](=[O:54])[C@@H:29]([C@@H:34]([C:44](=[O:53])[NH:45][O:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[CH2:35]/[CH:36]=[CH:37]/[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)C1(NC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)C1(N)CCCC1)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
A solution of 0.69 g of (E)-2′-[(1-(9-fluorenylmethyloxycarbonylamino)-1-cyclopentyl)carbonyl]-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in a mixture of 6.4 ml of dichloromethane and 1.6 ml of piperidine was stirred at room temperature for 1 hour. The solution was evaporated and the residue was treated with diethyl ether. The ethereal solution was filtered and evaporated. Chromatography on silica gel using methanol/dichloromethane (1:33) for the elution followed by evaporation gave 0.36 g of (E)-2′-[(1-amino-1-cyclopentyl)carbonyl]-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a white foam.
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]([NH:15][C@H:16]([C:24]([OH:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])=O)C1C=CC=CC=1.[ClH:27]>CO.CN(C)C=O.[Pd]>[ClH:27].[NH2:11][CH2:12][C:13]([NH:15][C@H:16]([C:24]([OH:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14]
Reactant: O=C(CNC(=O)OCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
23 g of benzyloxycarbonyl-glycyl-phenylalanine are dissolved in 250 ml of a methanol/dimethylformamide mixture (1:1) and submitted to hydrogenation by adding 1 g of palladium/charcoal (5% of Pd) (Pd/C) as the catalyst. The pH is kept constant at 4.5 by adding methanolic hydrochloric acid. After removal of the catalyst, the filtrate is concentrated in vacuo and the residue is precipitated from methanol by adding ether.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH2:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH:27](C)[CH3:28]>CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>[C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CCCCCO
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CC(C)[O-]
Agent: [Al+3]
Product: CCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 2 h
Yield: 96.3 %

Procedure:
Methyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate (256 g, 0.88 mole) and isooctanol (133 g, 0.91 mole) are added to a laboratory reactor equipped with the necessary auxiliary equipment. The mixture is heated to 85 C under a vacuum of 30 mmHg. After fifteen minutes, the vacuum is released and aluminum isopropoxide (1.77 g, 0.0087 mole, Rhone-Poulenc, Manalox 130) is added. The reaction mass is heated to 130 C while under a vacuum of 75 mmHg. After two hours, the reaction mass is heated to 165 C while under a vacuum of 30 mmHg for one hour. The excess isooctanol is removed by vacuum distillation at 165 C. The title compound (331 g, 97% yield) is obtained as a light yellow oil whose assay is 97% as judged by calibrated gas chromatography.
Reaction SMILES: I[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[I:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[N:14]=[CH:13][C:12]=1[OH:19]>CC(C)=O>[CH2:2]([O:19][C:12]1[C:11]([I:10])=[CH:16][C:15]([O:17][CH3:18])=[N:14][CH:13]=1)[CH3:3]
Reactant: CCI
Reactant: COc1cc(I)c(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cnc(OC)cc1I
Temperature: 80 °C
Reaction time: 8 h

Procedure:
At 0° C., 304 mg (1.95 mmol, 1.3 eq.) of iodoethane and 415 mg (3.0 mmol, 2.0 eq.) of potassium carbonate were added to a solution of 405 mg (1.5 mmol) of 4-iodo-6-methoxypyridin-3-ol in 10 ml of acetone and the mixture was stirred at 80° C. overnight and concentrated under reduced pressure. The residue was triturated with water, filtered and dried under reduced pressure. Yield: 322 mg (purity 93%, 72% of theory)
Reaction SMILES: [F:1][C:2]1([F:11])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.[Br:12]Br>C(Cl)(Cl)(Cl)Cl.O.[Fe]>[Br:12][C:9]1[CH:8]=[CH:7][C:5]2[O:6][C:2]([F:1])([F:11])[O:3][C:4]=2[CH:10]=1
Reactant: FC1(F)Oc2ccccc2O1
Reactant: BrBr
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: FC1(F)Oc2ccc(Br)cc2O1
Temperature: 0 °C
Yield: 49.4 %

Procedure:
A mixture of 15.8 grams (0.1 mole) of 2,2-difluoro-1,3-benzodioxole in 200 mL of carbon tetrachloride was stirred, and 2.8 grams (0.05 mole) of iron powder was added. The reaction mixture was cooled to 0° C., and 5.2 mL (0.1 mole) of bromine was added during a 20 minute period. Upon completion of addition the reaction mixture was cautiously warmed to 75° C. where it was stirred for one hour and then was allowed to cool to ambient temperature where it was stirred for 18 hours. The reaction mixture was taken up in 200 mL water and stirred for 20 minutes. The organic layer was separated and washed with water and then with two portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was distilled under high vacuum to yield 11.7 grams of 5-bromo-2,2-difluoro-1,3-benzodioxole. The nmr spectrum was consistent with the proposed structure. The reaction was repeated several times.
Reaction SMILES: [NH2:1][C:2]1N(C2C=CC=CC=2OC)[N:5]=[CH:4][C:3]=1[C:15]#N.[F:17][C:18]([F:23])([F:22])[CH2:19][NH:20][NH2:21]>>[NH2:5][C:4]1[N:20]([CH2:19][C:18]([F:23])([F:22])[F:17])[N:21]=[CH:15][C:3]=1[C:2]#[N:1]
Reactant: NNCC(F)(F)F
Reactant: COc1ccccc1-n1ncc(C#N)c1N
Product: N#Cc1cnn(CC(F)(F)F)c1N

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carbonitrile but substituting 1-(2,2,2-trifluoroethyl)hydrazine provided the title compound. 400 MHz 1H NMR (CDCl3) δ 7.60 (s, 1H), 4.59 (m, 2H), 4.40 (brs, 2H).
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[F:23][C:24]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][C:25]=1[NH2:26]>>[NH2:26][C:25]1[CH:27]=[CH:28][C:29]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:30][C:24]=1[F:23]
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)c(F)c3)c(F)cn2c1=O
Yield: 9.8 %

Procedure:
Ethyl 8-(4-amino-3-fluoro-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (149 mg, 0.46 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (134 mg, 0.58 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (18 mg, 10%). ESI-MS m/z: 399 (M+H)+.
Reaction SMILES: C([N:9]1[CH2:18][C:17]2[C:16](=[O:19])[NH:15][C:14]3[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=3[C:12]=2[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.CC(O)C>O.OS(O)(=O)=O>[CH2:11]1[CH2:10][NH:9][CH2:18][C:17]2[C:16](=[O:19])[NH:15][C:14]3[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=3[C:12]1=2
Reactant: O=C(c1ccccc1)N1CCc2c(c(=O)[nH]c3ccccc23)C1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: O=c1[nH]c2ccccc2c2c1CNCC2

Procedure:
A solution of 7.7 g (0.025 m) of 3-benzoyl-1,2,3,4-tetrahydrobenzo[c][2,7]naphthyridin-5(6H)-one in 30 ml of water, 10 ml of H2SO4, and 200 ml of 2-propanol was refluxed for 20 hr. After cooling, the solid was filtered and recrystallized from water, mp 292°-295° C. By analysis, this material contains 0.7 mole of H2SO4 per mole of base and was used as is for alkylation.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]=[N:17][S:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])=[N:14][CH:15]=1>O1CCCC1.[Cl-].[NH4+]>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([NH:17][S:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH2:2][C:1]#[N:3])=[N:14][CH:15]=1
Reactant: CC(C)(C)S(=O)N=Cc1ccc(Br)cn1
Reactant: CC#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC(CC#N)c1ccc(Br)cn1
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
To a solution of Acetonitrile (0.142 g, 3.472 mmol) in dry tetrahydrofuran (10 mL) is added n-butyl lithium (0.222 g, 3.472 mmol) at −78° C. and stir for 30 minutes at same temperature followed by drop wise addition of solution of 2-Methyl-propane-2-sulfinic acid 5-bromo-pyridin-2-ylmethyleneamide (0.5 g, 1.736 mmol) in dry tetrahydrofuran (10 mL) and stirred the reaction at −78° C. for 1 h. Reaction mixture is diluted with aqueous ammonium chloride solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combi-flash chromatography using 80% ethyl acetate in hexane to afford the title compound (0.25 g): 1H-NMR (400 MHz, DMSO-d6) δ: 1.17 (s, 9H), 2.93-2.99 (m, 1H), 3.11-3.16 (m, 1H)-4.72-4.78 (m, 1H), 6.09 (d, J=9.24, 1H), 7.64 (d, J=8.44 Hz, 1H), 8.12-8.14 (dd, J1=2.36 Hz, J2=8.4 Hz, 1H), 8.674 (d, 2.24 Hz, 1H). LC-MS (m/z): [M+H]=330.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[OH:25]CCNN>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH2:24][OH:25])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: NNCCO
Reactant: CCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Product: OCCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reaction time: 0.5 h

Procedure:
Compound 7 was synthesised following similar procedures outlined in Example 31 (Compound 18), using 2-hydroxyethyl hydrazine instead of ethyl hydrazine in Step 3. As a slightly modified procedure, Step 3 was performed at 90° C. for 30 min in the microwave. The crude residue was purified by column chromatography (silica gel, gradient 10 to 50% ethyl acetate/isohexane), yielding Compound 7 as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1.O>C(O)C.COC(O)C.[Ni]>[CH3:1][C:2]1[N:3]=[C:4]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:5][C:6]=1[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1
Reactant: CCOC(=O)CNc1nc(C)c(Cc2ccc([N+](=O)[O-])cc2)s1
Agent: [Ni]
Agent: COC(C)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)CNc1nc(C)c(Cc2ccc(N)cc2)s1
Yield: 72.8 %

Procedure:
9.2 g of ethyl (4-methyl-5-(4-nitrobenzyl)thiazol-2-yl)aminoacetate in 500 ml of an ethanol/methoxyethanol mixture are hydrogenated at normal pressure and room temperature in the presence of Raney nickel. After filtration of the catalyst and concentration of the reaction medium, a brown oil is obtained which is taken up with acidified water, the aqueous phase is extracted with chloroform and then rendered basic and the precipitate obtained is filtered off to give 6.1 g of ethyl (4-methyl-5-(4-aminobenzyl)thiazol-2-yl)aminoacetate in the form of a brown solid melting at 116° C.