Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].[CH2:5]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])[CH3:6].Cl.C([O-])(=O)C.[Na+].[CH2:20]([CH:22](C(C)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:21].[OH-].[K+]>C(O)C.O>[CH2:5]([C:7]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:8]=1[NH:9][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]2[CH3:21])[CH3:6]
Reactant: CCc1ccccc1N
Reactant: CCOC(=O)C(CC)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1[nH]c2c(CC)cccc2c1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 11.5 %

Procedure:
A solution of sodium nitrite (6.24 g, 90.64 mmol) was added dropwise to a mixture of 2-ethyl aniline (10.2 mL, 82.4 mmol), conc.HCl (20 mL) and water (30 mL) at −5° C. After the addition, the mixture was stirred at 0° C. for 15 min and brought to pH 3-4 by addition of sodium acetate. In a separate flask, a solution of ethyl α-ethylacetoacetate (14.6 mL, 90.64 mmol) in ethanol (50 mL) at 0° C. was treated with a solution of potassium hydroxide (5.08 g, 90.64 mmol) in water (20 mL) followed by addition of ice. The diazonium salt was immediately added to this alkaline solution. The mixture was adjusted to pH 5-6 by adding sodium acetate and stirred at 0° C. for 3 h. The solution was kept overnight at 4° C. and extracted with ethyl acetate, washed with brine, dried over magnesium sulfate and most of the solvent removed. The crude mixture was added dropwise to a solution of ethanolic HCl (50 mL) at 78° C. and stirred for 2 h at 78° C. The mixture was evaporated and chromatographed over silica gel eluting with ethyl acetate/hexane (3%) to afford the title compound (2.2 g, 11%). 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.48 (d, J=8 Hz, 1H), 7.12 (d, J=6.8 Hz, 1H), 7.06 (t, J=7.2 Hz, 1H), 4.38 (q, J=7.3 Hz, 2H), 2.82 (q, J=7.6 Hz, 2H), 2.58 (s, 3H), 1.40 (t, J=7.2 Hz, 3H), 1.33 (t, J=7.6 Hz, 3H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][C:3]=1[CH2:17][CH2:18][OH:19].[OH-].[K+].I[CH3:23]>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:16])[CH3:15])=[CH:4][C:3]=1[CH2:17][CH2:18][O:19][CH3:23]
Reactant: CI
Reactant: C[Si](C)(C)CCOCOc1ccc(Br)c(CCO)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COCCc1cc(OCOCC[Si](C)(C)C)ccc1Br
Reaction time: 16 h
Yield: 59 %

Procedure:
{2-[4-Bromo-3-(2-methoxy-ethyl)-phenoxymethoxy-ethyl}-trimethyl-silane: 2-[2-Bromo-5-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-ethanol (1.9 g, 6.0 mmol) was added to a solution of potassium hydroxide (1.35 g, 24 mmol) in DMSO (16 mL). Iodomethane (1.12 mL, 18 mmol) was added, and the solution stirred for 16 h. The reaction was diluted with water (50 mL) and extracted with ether (2×40 mL). Organics were washed with brine (40 mL), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (10% ether/hexanes) gave 1.28 g of {2-[4 bromo-3-(2-methoxy-ethyl)-phenoxymethoxy]-ethyl}-trimethyl-silane as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.40 (d, 1H, J=8.7 Hz), 6.96 (d, 1H, J=3.0 Hz), 6.80 (dd, 1H, J=8.7, 3.0 Hz), 5.18 (s, 2H), 3.74 (t, 2H, J=8.4 Hz), 3.60 (t, 2H, J=7.2 Hz), 3.37 (s, 3H), 2.98 (t, 2H, J=7.2 Hz), 0.95 (t, 2H, J=8.4 Hz), −0.01 (s, 9H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:46][C:47]1[NH:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[NH:48]1[C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=[C:47]1[NH:46][C:35](=[O:37])[C@@H:34]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[CH2:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1nc2ccccc2[nH]1)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 63.2 %

Procedure:
A solution of triphenylphosphine (274 mg, 1.04 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (211 mg, 1.18 mmol). The resulting brownish-purple mixture was stirred at 0° C. for 5 min until the reaction mixture became homogeneous. The reaction mixture was then treated with 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared as in Example 3, 200 mg, 0.70 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminobenzimidazole (139 mg, 1.04 mmol) and pyridine (0.17 ML, 2.09 mmol), and the reaction mixture was allowed to stir at 25° C. for 20 h. The resulting reaction mixture was diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 75/25 hexanes/ethyl acetate) afforded N-(1H-benzoimidazol-2-yl)-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide (178 mg, 64%) as an of-white foam: [α]23589=26.7° (c=0. 105, chloroform); EI-HRMS m/e calcd for C21H21Cl2N3O (M+) 401.1062, found 401.1062.
Reaction SMILES: [C:1]([C:6]1[C:7]([Cl:19])=[C:8]([Cl:18])[C:9]2[O:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][C:10]=2[CH:17]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.[CH3:21]NC.C=O>C(O)(=O)C.CN(C)C=O>[Cl:19][C:7]1[C:6]([C:1](=[O:5])[C:2](=[CH2:21])[CH2:3][CH3:4])=[CH:17][C:10]2[CH2:11][CH:12]([C:14]([OH:16])=[O:15])[O:13][C:9]=2[C:8]=1[Cl:18]
Reactant: CNC
Reactant: CCCC(=O)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Agent: C=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C=C(CC)C(=O)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Temperature: 0 °C
Yield: 71.4 %

Procedure:
A stirred mixture of 5-butyryl-6,7-dichloro-2,3-dihydro-2-benzofurancarboxylic acid (12.0 g, 0.04 mole), dimethylamine hydrochloride (4.3 g, 0.052 mole), para-formaldehyde (1.9 g, 0.063 mole) and acetic acid (4 drops) was heated on a steam bath for 21/2 hours. Dimethylformamide (35 ml) was added and heating was continued for 11/2 hours. The reaction mixture was poured into ice water, extracted with ether, washed with water and dried over magnesium sulfate. The ether was evaporated in vacuo and the residue triturated with butyl chloride (100 ml) to give 9.0 g of 6,7-dichloro-2,3-dihydro-5-(2-methylenebutyryl)-2-benzofurancarboxylic acid which melted at 148° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.CN(C)/[CH:17]=[C:18](/[C:24](=[O:33])[C:25]1[CH:30]=[C:29]([I:31])[CH:28]=[CH:27][C:26]=1F)\[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>O>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@@H:3]([CH2:2][N:1]2[C:26]3[C:25](=[CH:30][C:29]([I:31])=[CH:28][CH:27]=3)[C:24](=[O:33])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17]2)[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn(C[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c2ccc(I)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-3-(Aminomethyl)-1-N-Boc-pyrrolidine (994 mg, 4.86 mmol) was added to the stock solution of (Z)-ethyl 3-(dimethylamino)-2-(3-iodobenzoyl)acrylate (Intermediate 24, 0.34M, 13 mL, 4.42 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dried in a vacuum oven for 1.5 h. The resulting residue was then dissolved in dimethylformamide (8 mL) and potassium carbonate powder (670 mg, 4.86 mmol) was added. The reaction mixture was heated at 60° C. for overnight then cooled to room temperature. Water (50 mL) was added and the suspension was extracted with ethyl acetate (3×50 mL). The organic layers were dried over sodium sulfate, and the solvent was removed in vacuo to give quantitative (S)-ethyl 1-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate as a brown sticky solid.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH:5]=[CH:4][CH:3]=[N:2]1>Cl.O1CCOCC1>[N:1]1([CH2:6][CH:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2cccn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1cnn(CC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
The title compound from Step B above (100 mg, 0.4 mmol) was dissolved in 4 M HCl in dioxane (4.0 mL) and stirred at RT for 1 h. The product was concentrated under reduced pressure and dried under high vacuum to give the title compound (i-28) (59 mg, 95%). ESI-MS calculated for C9H15N3: Exact Mass: 165.13. Found 166.12.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(OC([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]([O:23][CH3:24])=O)[CH2:16][CH2:15]1)=O)(C)(C)C.O.[OH-].[Na+]>C1COCC1.CCOCC>[CH3:24][O:23][CH2:21][CH2:20][CH:17]1[CH2:18][CH2:19][NH:14][CH2:15][CH2:16]1
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COCCC1CCNCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5 g (696.6 mmol) of LiAlH4 in 800 mL of THF at rt was carefully added 30 g (232.2 mmol) of 1-t-butoxycarbonyl-4-(methoxycarbonyl methyl)piperidine and the reaction mixture was stirred at rt for 24 h. To the reaction mixture was slowly added 30 mL of H2O over a period of 2 h, followed by 30 mL of a 15% NaOH solution and 30 mL of H2O. The mixture was diluted with ether, filtered, and the solids were triturated several times with ethyl acetate. The combined organic fractions were concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[CH:5]=[CH:6][C:7]([OH:9])=O.O=S(Cl)Cl.Cl.[NH2:19][N:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[O:22].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[CH:5]=[CH:6][C:7]([NH:19][N:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[O:22])=[O:9]
Reactant: Cc1ccc(C=CC(=O)O)cc1Cl
Reactant: NN1CC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C=CC(=O)NN2CC(=O)NC2=O)cc1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 3-chloro-4-methylcinnamic acid (50 g, 0.25 mole) was added dropwise SOCl2 (140 ml). The mixture was heated under reflux for 45 min. after the addition was complete. After stirring at room temperature for 1 hour the SOCl2 was removed in vacuo. Dry benzene was added and then removed in vacuo. The acid chloride residue was treated with 1 -aminohydantoin hydrochloride (42 g, 0.275 mole) in 350 ml of pyridine, then heated under reflux for 2 hr. After cooling slightly, the reaction mixture was poured into a mixture of 200 ml of con HCl and 1500 ml of ice. After standing overnight the product was removed by filtration and washed with H2O. Recrystallization from CH3NO2 provided analytical material which melted at 271°-273° (28 g, 38%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:46])=[C:11]([CH:43]=[CH:44][CH:45]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:41][CH3:42])=[C:20]([O:23][C@@H:24]3[CH2:28][N:27](C(OC(C)(C)C)=O)[C@H:26]([C:36](=[O:40])[N:37]([CH3:39])[CH3:38])[CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1>C(Cl)Cl>[Cl:8][C:9]1[C:10]([F:46])=[C:11]([CH:43]=[CH:44][CH:45]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:41][CH3:42])=[C:20]([O:23][C@@H:24]3[CH2:28][NH:27][C@H:26]([C:36](=[O:40])[N:37]([CH3:39])[CH3:38])[CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1C[C@@H](C(=O)N(C)C)N(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CN[C@H](C(=O)N(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (5 ml) was added to a solution of 4-(3-chloro-2-fluoroanilino)-6-[(2S,4S)-1-(tert-butoxycarbonyl)-2-(N,N-dimethylcarbamoyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline (0.17 g) in methylene chloride (10 ml) and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was evaporated under vacuum and the residue dissolved in methanol (saturated with ammonia)/methylene chloride, adsorbed onto silica and purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) (100/0 to 85/15). The fractions containing the required product were combined and evaporated under vacuum to give the title product as a colourless gum which crystallised on standing (0.13 g); 1H NMR Spectrum: (DMSO d6 and CD3COOD) 1.85-1.96 (m, 1H), 2.84-2.95 (m, 4H), 3.00 (s, 3H), 3.24-332 (m, 1H), 3.40-3.48 (m, 1H), 3.95 (s, 3H), 4.31 (m, 1H), 5.21 (m, 1H), 7.20-7.30 (m, 2H), 7.47-7.55 (m, 2H), 7.76 (s, 1H), 8.37 (s, 1H); Mass Spectrum: (M+H)+ 460.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+].[SH:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>CN(C=O)C.O>[OH:32][C:29]1[CH:30]=[CH:31][C:26]([S:25][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[O:10])=[CH:4][C:3]=2[N+:16]([O-:18])=[O:17])=[CH:27][CH:28]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1cccs1
Temperature: 80 °C
Yield: 79.2 %

Procedure:
The product of Example 240a (1.50 g, 5.63 mmol) was dissolved in DMF to which K2CO3 (1.55 g, 11.27 mmol), and 4-mercapto-phenol (711 mg, 5.634 mmol) were added. The reaction mixture was then heated to 80° C. for 2 hrs. At this point the reaction mixture was cooled to room temperature and diluted with water which was then extracted with ethyl acetate to isolate the desired compound (1.66 g, 79%).
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][N:3]=1.[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26][NH2:27]>>[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26]/[N:27]=[C:2]1\[NH:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=3)=[CH:9][C:8]\1=2
Reactant: FC(F)(F)c1ccc(-c2ccc3c(c2)C(Cl)=NCCO3)cc1
Reactant: COC(CN)OC
Product: COC(C/N=C1\NCCOc2ccc(-c3ccc(C(F)(F)F)cc3)cc21)OC

Procedure:
A solution of 5-chloro-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine (11.7 mmol) in 2,2-dimethoxyethanamine (20 mL) was heated at 100° C. for 1 hour. The reaction mixture was concentrated to give (Z)-2,2-dimethoxy-N-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-ylidene)ethanamine as an oil. The crude material was dissolved in toluene (80 mL) and PPTS (6.0 g) was added and the mixture was refluxed for 5 h. The reaction mixture partitioned between ethyl acetate and brine and filtered through celite. The organic layer was dried with sodium sulfate and concentrated before being purified by silica gel chromatography (Rf=0.15 in 2:1 hexanes/ethyl acetate) to give 10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine as a white solid (2.3 g, 60% over three steps). C18H13F3N2O×TFA. 331.1 (M+1). 1H NMR (DMSO) δ 8.53 (d, J=2.0 Hz, 1H), 7.99 (d, J=8.0 Hz, 2H), 7.91 (dd, J=8.0, 2.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 2H), 7.77 (d, J=12.0 Hz, 2H), 7.30 (d, J=8.8 Hz, 1H), 4.65 (m, 4H). 19F NMR (DMSO) δ −59.21 (s, 3F).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([C:7]#[N:8])=O.C(=O)(O)O.[NH2:17][NH:18][C:19]([NH2:21])=[NH:20].[OH-].[K+]>>[NH2:20][C:19]1[N:18]=[N:17][C:5]([C:4]2[CH:9]=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=2[Cl:12])=[C:7]([NH2:8])[N:21]=1
Reactant: N=C(N)NN
Reactant: N#CC(=O)c1cccc(Cl)c1Cl
Agent: O=C(O)O
Agent: [K+]
Agent: [OH-]
Product: Nc1nnc(-c2cccc(Cl)c2Cl)c(N)n1

Procedure:
There is disclosed an improved process for the preparation of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine which process comprises the step of reacting 2,3-dichlorobenzoylchloride with cuprous cyanide in presence of acetonitrile and a cosolvent to produce dichlorobenzoyl cyanide, said dichlorobenzoyl cyanide is reacted with aminoguanidine bicarbonate to produce an intermediate product, which is cyclized in presence of aqueous potassium hydroxide to produce 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine.
Reaction SMILES: [Na].[Cl:2][C:3]1[N:8]=[C:7](Cl)[C:6]([CH2:10][C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[CH:5][N:4]=1.[CH:18]([OH:21])([CH3:20])[CH3:19]>>[Cl:2][C:3]1[N:8]=[C:7]([O:21][CH:18]([CH3:20])[CH3:19])[C:6]([CH2:10][C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[CH:5][N:4]=1
Reactant: Cc1ccc(Cc2cnc(Cl)nc2Cl)cn1
Reactant: CC(C)O
Agent: [Na]
Product: Cc1ccc(Cc2cnc(Cl)nc2OC(C)C)cn1
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of 1.38 g (0.06 g-atom) of sodium metal in 25 ml of isopropanol was heated to reflux until complete dissolution of the metal. The alkoxide solution was cooled to -10° and treated dropwise with a solution of 15.0 g (60 mmol) of 2,4-dichloro-5-[(6-methyl-3-pyridinyl)methyl]pyrimidine prepared as in Example 1 in 60 ml of isopropanol. The resulting mixture was allowed to warm to room temperature over 18 hours and was then concentrated. The resulting oil was dissolved in ethyl acetate, filtered, washed with water, dried over magnesium sulfate, filtered, concentrated and dried under vacuum to give 14.5 g (0.052 mol, 87%) of 2-chloro-4-isopropoxy-5-[(6-methyl-3-pyridinyl)methyl]pyrimidine. Recrystallization from ethyl acetate and petroleum ether gave yellow crystals: m.p. 38°-42°.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]([O:9]C)=[O:8])[CH2:5][CH2:4][N:3]1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.O[Li].O>C1COCC1.O>[O:1]=[C:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][CH2:4][N:3]1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C1CCN(c2cccnc2)C1=O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCN(c2cccnc2)C1=O
Reaction time: 8 h
Yield: 102.6 %

Procedure:
To a stirred solution of 350 (514 mg, 2.33 mmol) in THF (20 ml) under nitrogen was added a solution of LiOH.H2O (147 mg, 3.50 mmol) in water (5 mL). The reaction mixture was stirred overnight, concentrated, diluted with a small amount of water, filtered, neutralized with 1N HCl (pH ˜5-6), and extracted twice with dichloromethane. The aqueous phase was concentrated, and the residue was triturated in methanol (with traces of acetone). After filtration, the mother liquid was concentrated and dried under high vacuum to afford title compound 351 (493 mg, quantitative yield, contaminated with salts) as a pale yellow sticky solid. MS (m/z): 207.1 (M+H)+−.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([NH:15][NH2:16])=[O:14])=[N:4][C:5](Br)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.COC(C1C(N)=CC(C(F)(F)F)=C(Br)N=1)=O.COC(C1C(N)=CC(C(F)(F)F)=CN=1)=O>>[NH2:1][C:2]1[C:3]([C:13]([NH:15][NH2:16])=[O:14])=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=1
Reactant: NNC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Agent: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Agent: COC(=O)c1ncc(C(F)(F)F)cc1N
Product: NNC(=O)c1ncc(C(F)(F)F)cc1N

Procedure:
The title compound was prepared analogously to Intermediate H by replacing 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) with 3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A3);
Reaction SMILES: C(OC([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:37])[C@@H:20]([NH:25][C:26]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH:32]=2)=[O:27])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:13]([OH:38])[CH2:12]1)=O)C1C=CC=CC=1.C(OCC)(=O)C.[H][H]>CO.[Pd]>[OH:38][CH:13]1[CH:14]([NH:18][C:19]([C@@H:20]([NH:25][C:26]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH:32]=2)=[O:27])[CH2:21][CH:22]([CH3:23])[CH3:24])=[O:37])[CH2:15][CH2:16][CH2:17][NH:11][CH2:12]1
Reactant: [H][H]
Reactant: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCN(C(=O)OCc2ccccc2)CC1O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCNCC1O
Yield: 97.6 %

Procedure:
To a solution of 4-{(S)-2-[(benzofuran-2-carbonyl)-amino]-4-methyl-pentanoylamino}-3-hydroxy-azepane-1-carboxylic acid benzyl ester of Example 78b (1.6 g) in methanol:ethyl acetate (50 mL: 100 mL) was added 10% Pd/C. The reaction was stirred under a balloon of hydrogen for 2 hours whereupon it was filtered and concentrated to provide the title compound (1.16 g): MS(EI) 387 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:4][N:3]=1.FC(F)(F)S(O[CH2:26][CH:27]([F:29])[F:28])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([N:14]2[CH2:19][CH2:18][N:17]([CH2:26][CH:27]([F:29])[F:28])[CH2:16][CH2:15]2)=[CH:4][N:3]=1
Reactant: COc1ccc2c(Cl)ncc(N3CCNCC3)c2c1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(Cl)ncc(N3CCN(CC(F)F)CC3)c2c1
Yield: 16.3 %

Procedure:
To a solution of 1-chloro-6-methoxy-4-(piperazin-1-yl)isoquinoline (0.2 g, 0.720 mmol) in DMF (5 ml) was added 2,2-Difluoroethyl trifluoromethanesulfonate (0.154 g, 0.720 mmol) followed by sodium carbonate (0.114 g, 1.080 mmol). The reaction mass was stirred until judged complete. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get desired compound (0.04 g, 15.93%) as semi solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.18-8.15 (d, J=12 Hz, 1H), 7.93 (s, 1H), 7.45-7.42 (d, J=12 Hz, 1H), 7.37 (s, 1H), 6.36-5.76 (tf, 1H), 3.97 (s, 3H), 3.10 (m, 4H), 2.84 (m, 4H); 19F NMR: δ ppm −118.59 (1F); MS: MS m/z 342.19 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)\[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[O-:30][C:31]#[N:32].[K+].C(O)(=O)C>C(O)C>[CH3:29][O:28][C:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19]/[C:12](=[C:6]2\[C:7](=[O:11])[NH:8][C:9]3[C:5]\2=[CH:4][CH:3]=[C:2]([NH:1][C:31]([NH2:32])=[O:30])[CH:10]=3)/[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:25][CH:24]=1)=[O:27]
Reactant: N#C[O-]
Reactant: COC(=O)c1ccc(N/C(=C2\C(=O)Nc3cc(N)ccc32)c2ccccc2)cc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1ccc(N/C(=C2\C(=O)Nc3cc(NC(N)=O)ccc32)c2ccccc2)cc1

Procedure:
560 mg of 6-amino-3-(Z)-[1-(4-methoxycarbonyl-anilino)-1-phenyl-methylidene]-2-indolinone, 236 mg of potassium cyanate and 3.8 ml of glacial acetic acid are dissolved in 20 ml of ethanol and refluxed for 1 hour. After this time the solvent is evaporated, the residue is taken up in methylene chloride, washed with water and dried over sodium sulphate. After evaporation, the product is dried in the desiccator.