Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1=[N:11][C:12]([CH3:14])=[N:13][N:6]1[C:5]2([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:15].[CH2:22]1N2CN3CN(C2)CN1C3.Cl>COCCOC>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:7]3=[N:11][C:12]([CH3:14])=[N:13][N:6]3[CH2:22][N:15]=[C:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: Cc1nc2n(n1)C(N)(c1ccccc1)c1cc(Cl)ccc1-2
Agent: Cl
Solvent: COCCOC
Product: Cc1nc2n(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Reaction time: 8 h
Yield: 40.5 %

Procedure:
To a stirring solution of 3.1 g (10.4 mmol) of 7-chloro-2-methyl-5-phenyl-5H-[1,2,4]triazolo[5,1-a]-isoindol-5-amine and 3.1 g (22 mmol) of hexamethylenetetramine (hexamine) in 75 ml of DME is added 1.5 ml of 4 N HCl (dioxane). A precipitate forms immediately and the two phase mixture is refluxed. After 5 hours another 1.0 g of hexamine is added and reflux is continued overnight. An additional 1.5 ml of the HCl solution is added after 12 hours and again after an additional 24 hours. After another 24 hours, thin layer chromatography (TLC) shows the disappearance of starting material. The mixture is filtered and the solvent is removed from the filtrate under vacuum. The residue is taken up in CHCl3 and applied to a 5×10 cm silica gel column (Baker 60-200 mesh). The column is eluted with CHC13 until all of the high Rf material (followed by TLC) is recovered. The solvent is removed in vacuo and the residue recrystallized from 20 ml of acetonitrile to yield 1.3 g of pure product: m.p. 150.5°-152° [concentration of the mother liquor gives an additional 0.2 g for a total yield of 1.5 g (46.6%)].
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:5]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C1COCC1.Cl>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:3][C:4]2[N:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[C:6]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[N:5]=2)=[O:30])=[CH:26][CH:27]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: Nc1nc(OCC(F)(F)F)cc(C(F)(F)F)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1nc(OCC(F)(F)F)cc(C(F)(F)F)n1
Reaction time: 0.33 h
Yield: 44.5 %

Procedure:
To a suspension of NaH (152 mg, 3.8 mmol, 60% dispersion in mineral oil) in anhydrous THF (2 mL) at room temperature was slowly added a solution of 2-amino-4-(trifluoromethyl)-6-(2,2,2-trifluoroethoxy)pyrimidine (0.50 g, 1.9 mmol) in anhydrous THF (2 mL) and the resulting mixture was stirred 20 min. To the mixture was added 4-trifluoromethylphenyl isocyanate (326 μL, 2.28 mmol) and the resulting mixture was allowed to stir at room temperature. After 18 h of stirring the reaction mixture was diluted with 2 N HCl (30 mL). The acidic mixture was extracted with ethyl acetate. The organics were combined, dried over MgSO4, filtered and concentrated. The resulting residue was mixed with ethyl acetate (30 mL), diluted with hexane (100 mL) and allowed to stand at room temperature. After 18 h the insoluble material was filtered and dried in a vacuum oven (50° C.) to afford 102 as a white solid (379 mg, 44% yield): m.p. 197-199° C.; 1H NMR (DMSO-d6) δ 10.76 (s, 1H), 10.71 (s, 1H), 7.72 (app s, 4H), 7.35 (s, 1H), 5.25-5.16 (q, 2H, J=8.9 Hz); ESI/MS 448 (M+H), 447 (M−H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([N:26](CC)[C:27](=O)[C:28](F)(F)F)[CH2:24][CH3:25])=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][CH2:27][CH3:28])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)N(CC)C(=O)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.1 %

Procedure:
To a solution of N-{1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propyl}-N-ethyl-2,2,2-trifluoroacetamide (131 mg, 0.245 mmol) in ethanol (5.0 mL) was added sodium tetrahydroborate (28 mg, 0.74 mmol) at room temperature. The mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on NH-silica gel eluting with a 30-80% ethyl acetate/n-hexane gradient mixture to give the title compound (35.4 mg, 0.081 mmol, 33%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([O:18][CH2:19][CH2:20][CH3:21])=[N:11][CH:12]=[C:13]([CH:17]=1)[C:14]([OH:16])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]1[OH:51].CCN(C(C)C)C(C)C>C(O)(=O)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([O:18][CH2:19][CH2:20][CH3:21])=[N:11][CH:12]=[C:13]([CH:17]=1)[C:14]([NH:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]1[OH:51])=[O:16]
Reactant: CCCOc1ncc(C(=O)O)cc1-c1ccc(Cl)cc1Cl
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A mixture of 23.5 mg (0.072 mmol) 5-(2,4-dichloro-phenyl)-6-propoxy-nicotinic acid, 29 mg (0.09 mmol) TBTU, 10 mg (0.086 mmol) (1R,2R)-2-amino-cyclohexanol and 47.8 mg (0.37 mmol) DIPEA in 1 DMF was shaken at room temperature over night. Acetic acid was added and purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/HCOOH. The combined product fractions were evaporated to yield 24.9 mg (85%) of the title compound. MS (m/e): 423.2 (MH+).
Reaction SMILES: Cl.C([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])(=O)C.O.[OH-].[Na+].C(O)(=O)C>CO>[Cl:25][C:21]1[C:20]([F:26])=[C:19]([CH:24]=[CH:23][CH:22]=1)[NH:18][C:9]1[C:8]2[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([OH:5])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 98.2 %

Procedure:
6-Acetoxy-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline hydrochloride from step 1 (33.5 kg, 69.6 mol) was suspended in methanol (198 kg). To the stirred suspension at 25° C. was added water (86 kg) and sodium hydroxide (31.5 kg, 32%). The resulting solution was stirred at 60° C. for 4.5 hours and then cooled to 25° C. Acetic acid (approximately 16.0 kg) was added until a pH of 5.5-6.0 was achieved at which point the product precipitates from solution. After the addition of further methanol (5.5 kg) the suspension was stirred for 90 minutes. The product was filtered then washed with 25% aqueous methanol (39.0 kg MeOH+17.0 kg Water) and then methanol (55.5 kg). The crude solid was dried under vacuum at 40° C. The crude solid was slurried with water (145 kg) and stirred for 2 hours at 65° C. The slurry was cooled to 20° C. and filtered. The filter cake was washed with methanol (2×21.5 kg), then dried under vacuum at 40° C. to give a the title product as a light brown solid (21.85 kg, 98%); 1H NMR: 3.95 (s, 3H), 7.19 (s, 1H), 7.23 (dd, 1H), 7.42 (dd, 1H), 7.50 (dd, 1H), 7.64 (s, 1H), 8.32 (s, 1H), 9.43 (s, 1H), 9.67 (br.s, 1H); Mass Spectrum: 320.4, 322.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:20])[C:10]([C:12]1[CH:13]=[CH:14][C:15]([S:18][CH3:19])=[N:16][CH:17]=1)=[O:11].C([O:25]O)(C)(C)C.CC(C)(CC(C)C)C.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C1(C)C=CC=CC=1.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:10]([C:12]2[CH:13]=[CH:14][C:15]([S:18][CH3:19])=[N:16][CH:17]=2)=[O:11])[CH2:20][O:25]1
Reactant: C=C(C(=O)c1ccc(SC)nc1)c1ccc(F)cc1F
Reactant: CC(C)(C)OO
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(C)CC(C)(C)C
Product: CSc1ccc(C(=O)C2(c3ccc(F)cc3F)CO2)cn1

Procedure:
A solution of the product of part (iv) (3.8 g, 13 mmol) in toluene (40 ml) was treated with a solution of t-butylhydroperoxide in 2,2,4-trimethylpentane (3M, 4.7ml, 14 mmol) followed by a solution of benzyltrimethylammonium hydroxide in methanol (40%, 100 μl). After 1 hour at room temperature the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (100 ml) and water (50 ml). The organic phase was separated, dried (MgSO4) and evaporated under reduced pressure to give the title compound as a colourless oil, (3.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:65]=[CH:64][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:65]=[CH:64][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)cc2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.2 %

Procedure:
To a solution of 59 mg (0.3 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 91 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 2 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:9) to give 65 mg white solid (42%). MS (ISP) 479.4 (M+H)+.
Reaction SMILES: [C:1]([N:3]=[C:4]([N:12]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])OC1C=CC=CC=1)#[N:2].[C:24]([O:28][C:29]([NH:31][CH:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([N:3]=[C:4]([N:12]([CH2:19][CH:20]=[C:21]([CH3:22])[CH3:23])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:34]1[CH2:35][CH2:36][CH2:37][CH:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:33]1)#[N:2]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: CCOC(=O)CN(CC=C(C)C)C(=NC#N)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC=C(C)C)C(=NC#N)N1CCCC(NC(=O)OC(C)(C)C)C1

Procedure:
Prepared by reacting cyanimino-[N-(3-methyl-2-buten-1-yl)-N-(ethoxy-carbonylmethyl)-amino]-phenyloxy-methane with 3-(tert.-butyloxycarbonylamino)-piperidine in the presence of potassium carbonate in N,N-dimethylformamide at ambient temperature.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.Cl[C:16]1[C:21]([Cl:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1>>[Cl:22][C:21]1[C:16]([O:14][C:10]2[CH:9]=[C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH:13]=[CH:12][CH:11]=2)=[N:17][CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[CH:20]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Reactant: CN1CCN(c2cccc(O)c2)CC1
Product: CN1CCN(c2cccc(Oc3ncc([N+](=O)[O-])cc3Cl)c2)CC1

Procedure:
3-(4-Methylpiperazin-1-yl)phenol was reacted with 2,3-dichloro-5-nitro pyridine (as obtained in preparation 1), to obtain 1-(3-(3-chloro-5-nitropyridin-2-yloxy)phenyl)-4-methylpiperazine which was further converted to the title compound as per the procedure described in preparation 2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12]>CO.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Product: COc1cccc(N)c1N
Reaction time: 1 h

Procedure:
To a solution of 2-amino-3-nitroanisole (465 mg, 2.94 mmol) in methanol (50 mL) was added palladium on carbon (10% Pd, 100 mg). The mixture was then placed under an atmosphere of hydrogen gas (1 atm) and was stirred for one hour. The mixture was then filtered through celite and concentrated to give 2,3-diaminoanisole as a yellow foam in a yield of 400 mg (98%). 1H NMR (CDCl3) δ 3.45 (br s, 411 (NH)), 3.84 (s, 3H), 6.40 (m, 2H), 6.67 (t, 1H, J=7.8 Hz)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[C:15]1(C)[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C=C>[CH2:20]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][OH:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1)[CH:15]=[CH2:16]
Reactant: O=C(O)c1ccc(CO)c([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C=CCO
Product: C=CCOC(=O)c1ccc(CO)c([N+](=O)[O-])c1

Procedure:
In a 100 mL round bottom flask was placed 4-hydroxymethyl-3-nitrobenzoic acid (1.97 g, 10 mmol). Allyl alcohol (20 mL) was added, followed by p-toluenesulfonic acid (0.190 g, 1 mmol). The mixture was heated to reflux for 24 hr., at which time all the volatiles were removed in vacuo. The residue was taken up in EtOAc and washed with sat'd KHCO3. The organic layer was dried over MgSO4 and concentrated to afford the title compound as a cream colored solid; 2.4 g (100%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[CH3:16]N1C=CCN(C2C=CC(C)=CC=2)N1>CCOCC>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=1[C:6]([O:8][CH3:16])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: Cc1ccc(N2CC=CN(C)N2)cc1
Solvent: CCOCC
Product: COC(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
2,6-Dinitrobenzoic acid (10.6 grams) is suspended in ether (125 ml.) at 0°C. 1-Methyl-3-p-tolyltriazine (8.2 grams) in ether (75 ml.) is added dropwise to the stirred reaction mixture in an ice bath. The reaction mixture is stirred at 0° for 1 hour and at room temperature for 1 hour. The reaction mixture is diluted to 1 l. with ether and the insoluble product collected by filtration. Recrystallization from methanol gives colorless crystals (3.65 grams, melting point 150°-151.5°). An additional 4.1 grams of product are obtained from the filtrate.
Reaction SMILES: [CH2:1]([N:4]([CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2OS(C(F)(F)F)(=O)=O)[O:10][CH2:9]1)[CH2:5][CH2:6][CH3:7])[CH:2]=[CH2:3].[Li+].[Cl-].[CH3:28][Sn](C)(C)C.CN([CH:36]=[O:37])C>C1COCC1.CCCCCC.Cl[Pd]Cl>[C:36]([C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[CH2:17][CH:8]([N:4]([CH2:1][CH:2]=[CH2:3])[CH2:5][CH2:6][CH3:7])[CH2:9][O:10]2)(=[O:37])[CH3:28]
Reactant: CN(C)C=O
Reactant: C[Sn](C)(C)C
Reactant: C=CCN(CCC)C1COc2cccc(OS(=O)(=O)C(F)(F)F)c2C1
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCN(CCC)C1COc2cccc(C(C)=O)c2C1
Temperature: 120 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
3-(N-Allyl-N-n-propylamino)-5-trifluoromethanesulfonyloxychroman (0.28 g, 0.74 mmol), LiCl (0.097 g, 2.3 mmol), PdCl2 (dppf) (0.031 g, 0.04 mmol) and 2.6-di-t-butyl-4-methylphenol t-butyl-4-methylphenol (0.005 g) were dissolved in DMF (5.0 mL) in a three-necked round-bottom flask (50 mL) with a magnetic stirrer. The flask was evacuated, followed by inlet of CO (three times). Tetramethyltin (0.12 mL, 0.89 mmol) was added and then the mixture was stirred under an atmosphere of CO (1 arm) at 120° C. (oilbath temp) for 4 hours. The solvent was evaporated, the residue was partitioned between aqueous NH3 (2M) and CH2Cl2 (3×15 mL) and the organic phases were dried (Na2SO4), filtered and concentrated in vacuo. Column chromatography on silica with THF-n-hexane (1:9) as eluent afforded 5-acetyl-3-(N-allyl-N-n-propylamino)chroman (0.078 g, 39% yield) as an oil. The base was precipitated from an ether solution by adding a slight excess of HCl (approx. 3M in ether). The crude salt was collected and dried in vacuo at 40° C. to give a white amorphous powder. Mp 125°-127° C. PdCl2 (dppf)=dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Br:18])[C:3]=1[NH:19][C:20]([C:22]1[C:23]([O:38][CH3:39])=[C:24]([N:28]([CH3:37])[C:29]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1)=[O:21].[H-].[Na+].I[CH3:43].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])[CH:5]=[C:4]([Br:18])[C:3]=1[N:19]([CH3:43])[C:20]([C:22]1[C:23]([O:38][CH3:39])=[C:24]([N:28]([CH3:37])[C:29]([C:31]2[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: CI
Reactant: COc1c(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1N(C)C(=O)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C(=O)N(C)c2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1N(C)C(=O)c1ccncc1
Reaction time: 0.5 h

Procedure:
To a solution of N-[3-[[2,6-dibromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-methyl-pyridine-4-carboxamide (0.100 g, 0.145 mmole) in N,N-dimethylformamide (4 ml) was added sodium hydride (55% suspension in oil, 0.0067 g, 0.153 mmole). After the gas evolution had stopped, iodomethane (0.010 ml, 0.023 g, 0.160 mmole) was added. After 0.5 hour, the reaction mixture was poured on to water (15 ml) and the product was extracted with ethyl acetate. The organic solution was washed with water, then brine and dried over sodium sulfate. After removal of the solvent the crude was purified by column chromatography over silica gel using ethyl acetate-cyclohexane to yield the title compound (Compound G17 of Table G) as amorphous material showing by LC-MS analysis under the conditions 6 (described hereafter) a retention time of 1.09 min and a M+H+ mass of 700.
Reaction SMILES: [NH3:1].[C:2]([C:6]1[N:10]2[CH:11]=[CH:12][N:13]=[C:14](Cl)[C:9]2=[C:8]([C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:23]3)=[CH:18][CH:17]=2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3]>N.CC(O)C>[C:2]([C:6]1[N:10]2[CH:11]=[CH:12][N:13]=[C:14]([NH2:1])[C:9]2=[C:8]([C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:23]3)=[CH:18][CH:17]=2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(Cl)nccn12
Reactant: N
Solvent: CC(C)O
Product: CC(C)(C)c1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(N)nccn12
Temperature: 110 °C

Procedure:
Gaseous NH3 was condensed into a cooled (−78° C.) solution of 7-(3-tert-butyl-8-chloroimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoline (92.5 mg, 0.224 mmol) in NH3/i-PrOH (2M, 5 mL) in a pressure tube until the volume had doubled. The tube was sealed and heated to 110° C. for 21 h. After excess NH3 and i-PrOH were removed in vacuo, the residue was suspended between CH2Cl2 and water, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with brine (3×25 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with MeOH (7N NH3):CH2Cl2 1%→2%], affording the title compound, as a fine yellow solid. 1H NMR (CDCl3, 400 MHz) δ 1.25 (s, 914), 5.18 (s, —NH2), 7.08 (d, J=4.8 Hz, 1H), 7.45-7.51 (m, 1H), 7.51-7.57 (m, 3H), 7.90-7.97 (m, 3H), 8.17-8.22 (m, 2H), 8.27 (d, J=8.4 Hz, 1H), 8.42-8.44 (m, 1H); MS (ES+): m/z 394.1 (25) [MH+]; HPLC: tR=2.5 min (OpenLynx, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[NH:7][C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3.[H-].[Na+].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.O>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[N:7]([CH2:23][CH2:22][CH2:21][CH2:20][Br:19])[C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3
Reactant: BrCCCCBr
Reactant: Nc1ccc2c3c(cccc13)C(=O)NC2=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2c3c(cccc13)C(=O)N(CCCCBr)C2=O
Temperature: 25 °C

Procedure:
A suspension of 10.6 g of 6-amino-1H-benz[de]-isoquinoline-1,3(2H)-dione in 250 ml of dimetnylformamide was stirred as 2.6 g of 50% sodium hydride in mineral oil was added. The initial orange suspension turned deep red in color. After ten minutes, a solution of 27 g of 1,4-dibromobutane in 50 ml of dimethylformamide was added. A slightly exothermic reaction was noted, and a deep red solution resulted. The mixture was then stirred at room temperature for sixteen hours, and drowned into 600 ml of cold water. A tarry brown precipitate was obtained, and on standing, bright yellow crystals developed in the supernatant. These were collected and recrystallized from aqueous alcohol to yield the pure title compound mp 175°-176° C. The brown precipitate required several recrystallizations from aqueous alcohol to afford more of the pure title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C@H:15]([CH2:19][N:20]2[CH2:23][CH:22]([OH:24])[CH2:21]2)[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:6][CH:7]=1.[OH:25]OS([O-])=O.[K+].[OH2:31]>CO.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C@H:15]([CH2:19][N:20]2[CH2:21][CH:22]([OH:24])[CH2:23]2)[CH2:14][CH2:13][CH2:12]3)(=[O:25])=[O:31])[CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C[C@@H]2CCCc3cc(Sc4cccc(F)c4)ccc32)C1
Reactant: O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=S(=O)(c1cccc(F)c1)c1ccc2c(c1)CCC[C@H]2CN1CC(O)C1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a stirred solution of 1-[(R)-6-(3-fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-azetidin-3-ol (0.08 g, 0.23 mmol) in MeOH (4 mL) was added a solution of OXONE™ (0.307 g, 0.5 mmol) in 2.5 mL water. The reaction mixture was stirred at room temperature for 36 hours. The mixture was taken up in EtOAc, and the organic layer was washed with 1.5 M aqueous sodium carbonate, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (hexanes/EtOAc/MeOH 5:4:1 to give 0.06 g of 1-[(R)-6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-azetidin-3-ol, MS M+H=376.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH:9]([OH:11])[CH3:10])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:18]I>O>[C:9]([C:4]1[N:3]=[C:2]([Cl:1])[C:7]([OH:8])=[C:6]([I:18])[CH:5]=1)(=[O:11])[CH3:10]
Reactant: II
Reactant: CC(O)c1ccc(O)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)c1cc(I)c(O)c(Cl)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 38 %

Procedure:
2-Chloro-3-hydroxy-6-(1-hydroxyethyl)pyridine (7.19 g, 41.4 mmole) was dissolved in 80 ml of water containing potassium carbonate (17.2 g, 124 mmole) in a 200 ml one neck round bottom flask. The solution was treated with iodine (31.5 g, 124 mmole) and was stirred for 6 h at room temperature. The mixture was quenched with saturated sodium thiosulfate and the pH was adjusted to 2 with 12 N hydrochloric acid. The precipitate was collected, was washed with water, and was dried. The yellow solid was further washed with diethyl ether to provide 4.68 g (38%) of 6-acetyl-2-chloro-3-hydroxy-4-iodo-pyridine as a pale tan solid (Melting Point: 223-224° C.).