Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C(C1C=C(B(O)O)C=CC=1)=O.[N+:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)([O-:34])=[O:33]>>[CH3:10][N:5]1[C:4]2[CH:11]=[CH:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:14][C:3]=2[C:2]([C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([N+:32]([O-:34])=[O:33])[CH:40]=2)=[N:8][CH2:7][C:6]1=[O:9]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Agent: O=Cc1cccc(B(O)O)c1
Product: CN1C(=O)CN=C(c2cccc([N+](=O)[O-])c2)c2cc(-c3ccccc3)ccc21
Yield: 26 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using 3-formylbenzene boronic acid, we used 3-nitrophenyl boronic acid. The title compound (60 mg) was obtained as a beige solid, (yield=26%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:9]([OH:11])=O)[S:7][CH:8]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]([NH2:36])=[O:35])[C:29](=[O:37])[CH2:28]2.Cl>CN(C)C=O.CN(C1C=CN=CC=1)C>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]([NH2:36])=[O:35])[C:29](=[O:37])[CH:28]2[C:9](=[O:11])[C:6]1[S:7][CH:8]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: CC(=O)c1csc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(=O)c1csc(C(=O)C2C(=O)N(C(N)=O)c3ccc(Cl)cc32)c1
Temperature: 25 °C
Yield: 22 %

Procedure:
A 0.78 g (4.59 mmoles) sample of 4-acetyl-2-thiophenecarboxylic acid (prepared according to Satonaka, H., Bull. Chem. Soc. Japan 56:2463 (1983)) was combined with 0.95 g (5.85 mmoles) of 1,1'-carbonyldiimidazole in 10 ml of N,N-dimethylformamide and stirred at room temperature under argon atmosphere. After two hours the reaction contents were transferred to an addition funnel and slowly added to a slurry of 0.88 g (4.18 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 1.38 g (11.28 mmoles) of 4-(N,N-dimethylamino)pyridine in 30 ml of N,N-dimethylformamide stirring at 5° C. (ice bath) under an inert atmosphere. The reaction contents were stirred for fifteen minutes at 5° C. after complete addition followed by twenty-four hours at room temperature. Pouring the reaction mixture into 110 ml of 0.3N hydrochloric acid cause the precipitation of a greenish-yellow solid. Filtration followed by sequential washing with 3N hydrochloric acid and water, provided the crude product which was recrystallized twice from acetic acid to give 0.34 g (0.94 mmoles, 22% yield) of pure 5-chloro-3-(4-acetyl-2-thenoyl)-2-oxindole-1-carboxamide as a greenish-yellow solvated complex with 0.2 equivalents of acetic acid, m.p. 230°-233° C.
Reaction SMILES: [OH:1][CH:2]1[CH:10]([N+:11]([O-])=O)[C:9]2[CH2:8][C:7](=[O:14])[CH:6]=[CH:5][C:4]=2[CH2:3]1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:11][CH:10]1[C:9]2[CH2:8][C:7](=[O:14])[CH:6]=[CH:5][C:4]=2[CH2:3][CH:2]1[OH:1]
Reactant: O=C1C=CC2=C(C1)C([N+](=O)[O-])C(O)C2
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC1C2=C(C=CC(=O)C2)CC1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
A mixture of 2-hydroxy-3-nitro-5-indanone (1.50 g, 7.80 mmol) and tin (II) chloride (5.25 g, 23.3 mmol) in ethanol(150 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.00 g, 79%). 1H NMR (CD3OD): δ 6.85 (d,1H), 6.45 (d, 1H), 2.95 (d, 2H), 2.60 (d, 2H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]([C:12]1C=C(O)C(=C[CH:18]=1)O)(C)(C)[CH3:9].S(CCC(OCCCCCCCCCCCC)=O)CCC(OCCCCCCCCCCCC)=O.O=O.C=C/C=C/C>>[CH2:9]1[CH:2]2[C:1]([O:6][C:4](=[O:5])[CH:3]2[CH2:18][CH:12]=[CH:8]1)=[O:7]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(C)c1ccc(O)c(O)c1
Agent: C=C/C=C/C
Agent: CCCCCCCCCCCCOC(=O)CCSCCC(=O)OCCCCCCCCCCCC
Agent: O=O
Product: O=C1OC(=O)C2CC=CCC12

Procedure:
3Me--THPA was produced by the liquid phase aeration method. Thus, the air in a 300 ml four-necked flask similar to the one used in Example 5 was replaced with nitrogen and, then, the flask was charged with 98 g of maleic anhydride, 300 ppm of p-tert-butylcatechol by way of auxiliary polymerization inhibitor and 800 ppm of dilauryl thiodipropionate by way of auxiliary polymerization inhibitor and the charge was melted at 60° C. Then, the internal atmosphere of the reaction system was replaced with nitrogen gas, and thereafter nitrogen gas containing 1 volume % of oxygen was passed into the reaction mixture at a rate of 5 ml/min throughout the reaction. Under this atmosphere, 374 g of crude trans-1,3-pentadiene of the same composition as that used in Example 1 was continuously added at 60° C. for 4 hours. Major portion of unreactive fractions was distilled off from the reaction mixture in the course of reaction. Thereafter, the reaction mixture was treated in the same manner as in Example 5 to give 164 g of 3Me--THPA. The investigation revealed no gels in the product.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][N:6]=[C:5](C#N)[CH:4]=1.C[Mg]I.C(=O)(O)[O-:15].[Na+].C[CH2:20][O:21][CH2:22][CH3:23]>C1C=CC=CC=1>[C:4]([C:5]1[CH:23]=[C:22]([O:21][CH3:20])[CH:8]=[CH:7][N:6]=1)(=[O:15])[CH3:3]
Reactant: CCOCC
Reactant: O=C([O-])O
Reactant: COc1ccnc(C#N)c1
Agent: C[Mg]I
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccnc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of 4-methoxy-2-pyridinecarbonitrile (5.35 g, 38.6 mmol) in benzene (50 ml) and ether (50 ml) cooled to 0° C. was added dropwise over 20 min a 2M slution of MeMgI in ether (23 ml, 46.3 mmol). After 0.5 h, the mixture was allowed to warm to ambient temperature, and stirring continued for 2 h. The mixture was cooled to 0° C. and 2M aqueous HCI (100 ml) added. The mixture was made basic with saturated aqueous sodium bicarbonate (˜80 ml) and the organic layer separated and dried (MgSO4). After removal of solvent, the residue was purified by flash chromatography eluting with ethyl acetate/hexane (1:5) to afford 3.60 g (60%) of 2-acetyl-4-methoxypyridine.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]1[S:12][C:13](=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=3[C:33]([F:36])([F:35])[F:34])=[C:20]([O:37][CH3:38])[CH:19]=2)[C:14](=[O:16])[N:15]=1)(C)(C)C.[ClH:40].C(OCC)C>C(OCC)(=O)C.CO>[ClH:40].[NH2:7][CH2:8][CH2:9][NH:10][C:11]1[S:12][C:13](=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=3[C:33]([F:35])([F:34])[F:36])=[C:20]([O:37][CH3:38])[CH:19]=2)[C:14](=[O:16])[N:15]=1
Reactant: COc1cc(C=C2SC(NCCNC(=O)OC(C)(C)C)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C=C2SC(NCCN)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 30 %

Procedure:
LC/MS (m/z) [M+1]+563.1 (calculated for C26H25F3N4O5S, 562.56). (2-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)-carbamic acid tert-butyl ester (0.09 g, 0.14 mmol) was dissolved in a 5/3 mixture of ethyl acetate/methanol (6 mL). To the reaction was then added aqueous 4.0N HCl (4 mL). The reaction mixture was stirred at room temperature for 2 days and the solvent evaporated in vacuo to yield a crude oil. Diethyl ether was added to the residue and the solvent evaporated in vacuo to give a solid which was recrystallized from MeOH and diethyl ether to yield compound as a solid (0.020 g, 30%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][CH:10]=1.[CH2:17]([O:19][C:20](=[O:30])[CH2:21][NH:22][C:23]1[C:28]([NH2:29])=[CH:27][CH:26]=[CH:25][N:24]=1)[CH3:18].C(OC(=O)CNC1C([N+]([O-])=O)=CC=CN=1)C>O1CCCC1.[Pd]>[CH2:17]([O:19][C:20](=[O:30])[CH2:21][NH:22][C:23]1[C:28]([NH:29][C:14]([C:12]2[S:13][C:9]([CH3:8])=[CH:10][CH:11]=2)=[O:15])=[CH:27][CH:26]=[CH:25][N:24]=1)[CH3:18]
Reactant: Cc1ccc(C(=O)Cl)s1
Reactant: CCOC(=O)CNc1ncccc1N
Agent: [Pd]
Agent: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(C)s1
Yield: 100.8 %

Procedure:
Under a nitrogen atmosphere, triethylamine (31.41 g, 0.311 mole) and 5-methyl-2-thiophenecarbonyl chloride (50 g, 0.311 mole) were added simultaneously, dropwise, to a stirred and chilled solution of freshly prepared N-[[3-amino]-2-pyridinyl]glycine ethyl ester (0.296 mole) by palladium/carbon reduction of N-[[3-nitro]-2-pyridinyl]glycine ethyl ester (66.98 g, 0.296 mole) in dry tetrahydrofuran (~1 liter). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate, the layers separated and the aqueous layer was again extracted with ethyl acetate. The combined organic layers were washed twice with a 5% potassium hydroxide solution, twice with a saturated sodium bicarbonate solution, twice with water, dried over magnesium sulfate, treated with charcoal, filtered, and evaporated under reduced pressure to give 95.3 g of a tan solid in quantitative yield. A 1.5-g portion of the solid was dissolved in hot absolute ethanol, filtered while hot, and brought to its cloud point by addition of water. Cooling to room temperature gave a solid which was collected by filtration, rinsed with water, and dried under high vacuum at room temperature overnight to give 1.11 g of title compound, mp 112°-115° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[C:13]([F:16])([F:15])[F:14].[N:17]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl.O>[NH:1]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[C:13]([F:16])([F:14])[F:15])[NH2:17]
Reactant: O=N[O-]
Reactant: Nc1ccc2[nH]c(=O)cc(C(F)(F)F)c2c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc2[nH]c(=O)cc(C(F)(F)F)c2c1
Temperature: -1 °C
Reaction time: 1 h

Procedure:
In a 250 mL rb flask a suspension of Compound 200 (structure 3 of Scheme XXXIII) (2.28 g, 10 mmol) in 10 mL conc. HCl was cooled to −1° C. and a solution of NaNO2 (0.40 g, 12 mmol) in water (5 mL) was added dropwise in 20 min. The dark yellow suspension was stirred at −1° C. for 1 h and then a solution of SnCl2.2H2O (5.2 g, 15 mmol) in conc HCl (10 mL) was added dropwise in 10 min. The light yellow suspension of Compound 793 was stirred at −1° C. for 2 h and then used directly or kept in a refrigerator at −1° C. until it was used (the crude compound can be stored for at least one month without decomposition).
Reaction SMILES: CN(C)[CH:3]=[O:4].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14](=[O:24])[CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17].[NH2:25][CH2:26][CH:27]([C:29]1[CH:34]=[C:33]([Cl:35])[C:32]([NH2:36])=[C:31]([Cl:37])[CH:30]=1)[OH:28]>C(OCC)(=O)C.CO.C(N(CC)CC)C>[NH2:36][C:32]1[C:31]([Cl:37])=[CH:30][C:29]([CH:27]([OH:28])[CH2:26][NH:25][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14](=[O:24])[CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:34][C:33]=1[Cl:35].[C:3]([O-:4])(=[O:28])/[CH:16]=[CH:15]\[C:14]([O-:13])=[O:24]
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Reactant: CN(C)C=O
Reactant: CC(CC(=O)OCCCCCCBr)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(CC(=O)OCCCCCCNCC(O)c1cc(Cl)c(N)c(Cl)c1)c1ccccc1
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
According to method I (dimethylformamide, 3 hours at 90° C.) from (6-bromo-1-hexyl)3-phenylbutanoate and 2-amino-1-(4-amino-3,5-dichlorophenyl)ethanol. Working up by means of chromatography (ethyl acetate/methanol/triethylamine 20:2:1). Recrystallized as the maleate from ethyl acetate. Melting point: 51°-59° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][CH:30]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[C:12]([C:17]([NH2:19])=[O:18])=[N:13][C:14]=1[CH2:15][CH3:16].N1(CO)C2C=CC=C[C:43]=2N=N1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C.O1CCCC1.C(O)C>[CH2:15]([C:14]1[N:13]=[C:12]([C:17]([NH2:19])=[O:18])[C:11]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:28][CH2:29][CH:30]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[CH2:31][CH2:32]3)=[CH:25][CH:26]=2)=[N:10][C:9]=1[NH:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[NH:1][CH3:43])[CH3:16]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1N[C@@H]1CCCC[C@@H]1N
Reactant: OCn1nnc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1N[C@@H]1CCCC[C@@H]1NC
Temperature: 25 °C
Reaction time: 7 h
Yield: 67.6 %

Procedure:
To a mixture of 5-{[(1R,2S)-2-aminocyclohexyl]amino}-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (62 mg), ethanol (5 mL), and tetrahydrofuran (3 mL) were added 1H-benzotriazol-1-yl methanol (18 mg) and sodium acetate (15 mg), followed by stirring at room temperature for 7 hours. Sodium triacetoxyborohydride (50 mg) was added thereto under ice-cooling, followed by stirring at room temperature for 12 hours. To the reactant were added ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution, followed by liquid separation. The organic phase was dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=500:10:1-200:10:1) to obtain 6-ethyl-5-{[(1R,2S)-2-(methylamino)cyclohexyl]amino}-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (43 mg) as a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:49])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4].[C:50]([O:54][C:55]([NH:57][CH2:58][C:59]([NH:61][CH2:62][C:63](O)=[O:64])=[O:60])=[O:56])([CH3:53])([CH3:52])[CH3:51]>O1CCCC1>[C:50]([O:54][C:55]([NH:57][CH2:58][C:59]([NH:61][CH2:62][C:63]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:49])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4])=[O:64])=[O:60])=[O:56])([CH3:53])([CH3:52])[CH3:51]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Yield: 74 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-oleamide and N-tert-butyloxycarbonyl-glycyl-glycine. Yield 74%. [α]D =+14.2° (c=1.00, tetrahydrofuran).
Reaction SMILES: [C:1]([C:3](=[C:7](SC)SC)[C:4]([NH2:6])=[O:5])#[N:2].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1.O.[NH2:26][NH2:27]>CCO>[NH2:2][C:1]1[NH:27][N:26]=[C:7]([NH:12][C:13]2[CH:18]=[N:17][C:16]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:15][CH:14]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NN
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: CSC(SC)=C(C#N)C(N)=O
Solvent: CCO
Solvent: O
Product: NC(=O)c1c(Nc2ccc(N3CCOCC3)nc2)n[nH]c1N
Temperature: 75 °C

Procedure:
Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 4-(5-amino-2-pyridinyl)morpholine (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((6-morpholinopyridin-3-yl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: O1CCOCC1.Cl.[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)=[CH:14][N:13]=[C:12]([C:29]2[CH:30]=[C:31]([CH:41]=[CH:42][CH:43]=2)[CH2:32][NH:33]C(=O)OC(C)(C)C)[C:11]=1[F:44])#[N:9]>ClCCl>[NH2:33][CH2:32][C:31]1[CH:30]=[C:29]([C:12]2[C:11]([F:44])=[C:10]([C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)=[CH:14][N:13]=2)[C:8]#[N:9])[CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2ncc(-c3ccc(Oc4ccccc4)cc3)c(C#N)c2F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)cnc(-c2cccc(CN)c2)c1F
Reaction time: 3 h

Procedure:
A 1 M dioxane solution of HCl (3 mL, 3.00 mmol) was added to a solution of tert-butyl 3-(4-cyano-3-fluoro-5-(4-phenoxyphenyl)pyridin-2-yl)benzylcarbamate (54.6 mg, 0.110 mmol) in dichloromethane (3 mL). After 3 h at room temperature, the mixture was concentrated and pumped under vacuum to give 2-(3-(aminomethyl)phenyl)-3-fluoro-5-(4-phenoxyphenyl)isonicotinonitrile as brown solid, assumed as bis-HCl salt (48 mg, 93% yield). 1H NMR (500 MHz, methanol-d4) δ ppm 8.80 (1H, s), 8.16 (1H, s), 8.08 (1H, br. s), 7.72 (2H, δ, J=8.25 Hz), 7.65 (2H, δ, J=3.85 Hz), 7.42 (2H, t, J=7.70 Hz), 7.20 (1H, t, J=7.29 Hz), 7.16 (2H, δ, J=7.97 Hz), 7.10 (2H, δ, J=7.97 Hz), 4.25 (2H, s); MS (ES+) m/z: 396 (M+H); LC retention time: 3.768 min (analytical HPLC Method A).
Reaction SMILES: BrCC.[CH2:4]([N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])C.CNC[C:14]1[S:15]C=[CH:17][CH:18]=1>C1(C)C=CC=CC=1.O.C(=O)(O)[O-].[Na+]>[CH2:7]([N:6]([CH3:4])[CH2:9][C:10]1[S:15][CH:14]=[CH:18][CH:17]=1)[CH3:8]
Reactant: CNCc1cccs1
Reactant: CCN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCBr
Solvent: Cc1ccccc1
Product: CCN(C)Cc1cccs1

Procedure:
Bromoethane (150 ml), triethylamine (7.3 ml) and N-methyl-2-thiophenemethanamine (21.2 g) were stirred at room temperature in toluene (212 ml) for 4 days. The solution was diluted with water, saturated with sodium bicarbonate and extracted with ethyl acetate. The organic extracts were distilled to give the title compound as an oil (13.6 g) b.p. 46° (16 mm).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:3]=12.[NH2:17][C:18]1[CH:23]=[C:22]([OH:24])[C:21]([CH3:25])=[CH:20][CH:19]=1>C(OCCO)C>[OH:24][C:22]1[CH:23]=[C:18]([NH:17][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[O:12][C:3]=23)[CH:19]=[CH:20][C:21]=1[CH3:25]
Reactant: N#Cc1cnc2c(oc3ccccc32)c1Cl
Reactant: Cc1ccc(N)cc1O
Solvent: CCOCCO
Product: Cc1ccc(Nc2c(C#N)cnc3c2oc2ccccc23)cc1O
Temperature: 80 °C
Yield: 72.1 %

Procedure:
A mixture of 200 mg (0.88 mmol) of 4-chlorobenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile and 120 mg (0.97 mmol) of 5-amino-o-cresol in 6 mL of 2-ethoxyethanol is heated at 80° C. for 15 hours and then at reflux temperature for 10 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is washed with saturated sodium bicarbonate, dried over sodium sulfate and filtered through a pad of diatomaceous earth. Concentration in vacuo yields 200 mg (72%) of a beige solid, mp 240° C. dec. 1HNMR (DMSO-d6): δ 2.13 (s, 3H), 6.61 (dd, 1H), 6.68 (d, 1H), 7.03 (d, 1H), 7.51 (t, 1H), 7.63–7.74 (m, 2H), 8.15 (d, 1H), 8.62 (s, 1H), 9.40 (s, 1H), 9.66 (s, 1H). MS (ES, positive ion mode): m/z calcd for C19H13N3O2: 315.3, found: 315.9 (M+H)+. Analysis for C19H13N3O2.0.2H2O Calcd: C:71.54; H:4.22; N:13.17 Found: C:71.39; H:4.31; N: 12.99.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[N:7]([O-])=O.[Na+].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>OS(O)(=O)=O.[Zn]>[C:12]1([CH:11]=[N:7][N:1]2[CH2:5][CH2:4][NH:3][C:2]2=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=N[O-]
Reactant: O=Cc1ccccc1
Reactant: O=C1NCCN1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [Zn]
Product: O=C1NCCN1N=Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A stirring solution of 65 g (0.75 mole) of 2-imidazolidinone in 2000 ml of 2N H2SO4 is cooled to 0° C. A 53 g (0.77 mole) portion of NaNO2 is added portionwise, over a 15 minute period, maintaining the temperature at 0° C. The resulting mixture is stirred at 0° C. for 2 hours. A 108 g (1.65 mole) portion of zinc dust is added portionwise, over a 1 hour period, maintaining the temperature at 0° C. The reaction is stirred at 0° C. for 0.5 hour and then at ambient temperature for 1 hour. The excess zinc is removed by filtration. The filtrate is treated all at once, with a solution of 80 g (0.75 mole) of benzaldehyde, in 400 ml of S.D.A. #32 and the resulting mixture is stirred hours at about 16 to 18 hours at ambient temperature. The solid is collected by filtration, washed with H2O, and air-dried to yield 124 g (87%) of 1-[(phenylmethylene)amino]-2-imidazolidinone.
Reaction SMILES: Br.C(O)(=O)C.C(OC([NH:16][CH2:17][C:18]([N:20]([CH2:22][CH2:23][CH2:24][P:25](=[O:28])([OH:27])[OH:26])[OH:21])=[O:19])=O)C1C=CC=CC=1.C(OCC)C>C(O)(=O)C>[NH2:16][CH2:17][C:18]([N:20]([CH2:22][CH2:23][CH2:24][P:25](=[O:26])([OH:28])[OH:27])[OH:21])=[O:19]
Reactant: O=C(NCC(=O)N(O)CCCP(=O)(O)O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NCC(=O)N(O)CCCP(=O)(O)O
Temperature: 25 °C
Yield: 32.6 %

Procedure:
48% Hydrogen bromide-acetic acid (1 ml) was added under ice-cooling to a solution of 3-[N-(N-benzyloxycarbonyl-aminoacetyl)-N-hydroxyamino]propylphosphonic acid (200 mg) in acetic acid (1 ml) and the reaction mixture was stirred at an ambient temperature for an hour. To the resultant mixture was added dry ethyl ether (20 ml) to precipitate an oil. The oil was separated, washed twice with dry ethyl ether (10 ml) and then dissolved in water (0.5 ml). The solution was adjusted to pH 4 with pyridine and ethanol (5 ml) was added thereto to give precipitates. The upper layer was removed by decantation and the precipitates was pulverized with ethyl ether (10 ml) to give 3-(N-aminoacetyl-N-hydroxyamino)propylphosphonic acid (40 mg) in the form of powder.