Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@H:40]2[CH2:45][CH2:44][CH2:43][N:42]([CH2:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)[CH2:41]2)=[O:37])=[O:30])[CH2:3]1.[C:53](OC(=O)C)(=[O:55])[CH3:54]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:53]([NH:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@H:40]2[CH2:45][CH2:44][CH2:43][N:42]([CH2:46][CH:47]3[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]3)[CH2:41]2)=[O:37])=[O:30])[CH2:3]1)(=[O:55])[CH3:54]
Reactant: N[C@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)N[C@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
To a solution of 22 mg of (2R)-1-{(2S,4S)-4-amino-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-N-{((3R)-1-cyclohexylmethyl-3-piperidyl)methyl}pyrrolidine-2-carboxamide in 1 ml of chloroform, 0.0089 ml of acetic anhydride and 0.0127 ml of pyridine were added at room temperature, followed by an hour's stirring at the same temperature. The reaction liquid was diluted with chloroform, washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After distilling the solvent off under reduced pressure, the resulting residue was purified with a preparative thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol=8/1), to provide 18 mg of the title compound as a white solid.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[C:6]1(=[O:10])[CH2:9][CH2:8][CH2:7]1>Cl>[CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[CH:9]1([CH2:6][OH:10])[CH2:7][CH2:8]1
Reactant: O=C1CCC1
Agent: Cl
Agent: OC1CCC1
Product: OCC1CC1

Procedure:
The processes so far described for the oxidation of cyclobutanol to cyclobutanone use customary oxidizing agents in organic synthesis. A comparison of the existing oxidation methods is given in DE 199 10 464. In general, these are oxidations carried out in homogeneous systems from which the desired cyclobutanone first has to be isolated by extraction or the like. These processes generally lead to large amounts of waste and also to high burdens of toxic reagents, for example when using CrO3/oxalic acid according to Org. Synth. 1981, 60, 20–25. In this process, the direct oxidation of the solution of cyclobutanol in aqueous hydrochloric acid obtained from the isomerization of cyclopropylmethanol is described. For the conversion of 49.5 g of cyclopropylmethanol (results in 14–16 g of cyclobutanone, yield 31–35%), approximately 1.2 l of strongly acidic, chromium-containing wastewater is formed.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:11](OC(=O)C)(=O)C.C(OCC)(OCC)OCC.[CH3:28][O:29][C:30]1[C:31]([NH2:36])=[CH:32][CH:33]=[CH:34][CH:35]=1>>[CH3:1][O:2][CH2:3][C:4]([C:5](=[CH:11][NH:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[O:29][CH3:28])[C:6]([O:8][CH3:9])=[O:7])=[O:10]
Reactant: COCC(=O)CC(=O)OC
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1N
Solvent: CCOC(OCC)OCC
Product: COCC(=O)C(=CNc1ccccc1OC)C(=O)OC
Yield: 59.7 %

Procedure:
Methyl 4-methoxyacetoacetate (43 ml, 0.33 mol), acetic anhydride (31 ml, 0.33 mol) and triethyl orthoformate (110 ml, 0.66 mol) were heated under reflux for 2 hours, then the excess triethyl orthoformate and the produced ethyl acetate were evaporated from the mixture under reduced pressure. o-Anisidine (43 ml, 0.35 mol) was added and ethanol (15 ml) was distilled over under atmospheric pressure. When cool, the mixture was poured slowly into hexane to produce methyl 2-methoxyacetyl-3-(2-methoxyphenylamino)acrylate (55 g, 59.5%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[CH2:5]2.[CH3:12][C:13]([CH3:15])=O.N>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][C:5]2=[C:13]([CH3:15])[CH3:12]
Reactant: CC(C)=O
Reactant: O=C1Cc2cc(O)ccc2N1
Agent: N
Solvent: CCO
Product: CC(C)=C1CNc2ccc(O)cc21
Yield: 94 %

Procedure:
A mixture of 20 g. 5-hydroxyindolinone, 80 ml. acetone and 80 ml. ethanol is saturated with gaseous ammonia and heated under reflux for 3 hours. After evaporation, the reaction mixture is filtered off with suction. There are obtained 27.7 g. of the title compound (94% of theory); m.p. 235° C.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.[CH2:14]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:15]1[O:17][CH2:16]1.C(N(CC)CC)C.O>CC(N(C)C)=O>[CH2:19]([O:18][CH2:14][C@H:15]([OH:17])[CH2:16][O:12][C:11]1[C:2]([Br:1])=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([CH3:13])[CH:5]=[CH:4]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc2c(Br)c(O)ccc2n1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc2c(Br)c(OC[C@@H](O)COCc3ccccc3)ccc2n1
Yield: 73 %

Procedure:
A solution of 5-bromo-2-methyl-6-quinolinol (30.1 g, 126 mmol), (R)-benzyl glycidyl ether (24.9 g, 152 mmol) and triethylamine (17.4 g, 172 mmol) in DMA (200 mL) was heated in a 95–98° C. oil bath for 2 days. The solution was cooled and poured into water (300 mL) while stirring. The tan precipitate formed was filtered, washed with water (100 mL) and dried in a vacuum oven to give 37 g (73%) of the title compound as a tan solid.
Reaction SMILES: C(OC[N:10]1[C:18]2[C:17]([NH2:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12]([C:24]#[C:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:31][CH2:30]2)=[CH:11]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd].CO.CS(C)=O>[CH2:20]([C:15]1[N:16]=[C:17]([NH2:19])[C:18]2[NH:10][CH:11]=[C:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:33][CH2:34]3)[C:13]=2[N:14]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCc1nc(N)c2c(n1)c(C#CCCCN1CCN(C(C)C)CC1)cn2COCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CS(C)=O
Solvent: CO
Solvent: CCO
Product: CCCCc1nc(N)c2[nH]cc(CCCCCN3CCN(C(C)C)CC3)c2n1
Yield: 35.5 %

Procedure:
5-((Benzyloxy)methyl)-2-butyl-7-(5-(4-isopropylpiperazin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (77 mg, 0.153 mmol) in ethanol (20 mL) was passed through the H-cube (settings: 45° C., full hydrogen, 1 mL/min flow rate and 10% palladium on carbon CatCart30 as the catalyst). A new 10% palladium on carbon CatCart30 cartridge was inserted into the H-cube and the solution was again passed through the H-cube (settings: 45° C., full hydrogen, 1 mL/min flow rate). The solution was evaporated in-vacuo to yield a white solid. The solid was dissolved in MeOH:DMSO (1:1) (1 mL) and purified by MDAP (Method B). the appropriate fraction was evaporated in-vacuo to yield the title compound as a white solid (21 mg).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]2[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([OH:27])=O)=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30]>>[C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]2[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:27])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1ccc(C2c3ccccc3CCC2c2ccccc2)cc1
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)C=Cc1ccc(C2c3ccccc3CCC2c2ccccc2)cc1

Procedure:
Prepared by coupling 7d and methylsulfonamide in accordance with Procedure 1, Method A described hereinabove. Yield (56%); 1H NMR (CDCl3) δ 7.63 (d, J=15.4 Hz, 1H), 7.14 (m, 8H), 6.83 (m, 3H), 6.46 (d, J=8.1 Hz, 2H), 6.26 (d, J=15.4 Hz, 1H), 4.37 (d, J=5.1 Hz, 1H), 3.46 (m, 1H), 3.34 (s, 3H), 3.13 (m, 2H), 2.16 (m, 1H), 1.88 (m, 1H); ESI m/z: 430 (M−H−, 100%).
Reaction SMILES: [C:1](=[O:18])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.[NH2:20][C:21]1[N:26]=[C:25]([C:27]2[CH:36]=[C:35]3[C:30]([CH2:31][CH2:32][N:33]([C:37]([O:39][CH:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)=[O:38])[CH2:34]3)=[CH:29][CH:28]=2)[CH:24]=[C:23]([N:46]2[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]2)[N:22]=1>>[NH2:20][C:21]1[N:26]=[C:25]([C:27]2[CH:36]=[C:35]3[C:30]([CH2:31][CH2:32][N:33]([C:37]([O:39][CH:40]4[CH2:45][CH2:44][N:43]([C:1]([O:2][CH:3]5[CH2:4][CH2:5][CH2:6][CH2:7]5)=[O:18])[CH2:42][CH2:41]4)=[O:38])[CH2:34]3)=[CH:29][CH:28]=2)[CH:24]=[C:23]([N:46]2[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]2)[N:22]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCCC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCNCC3)CC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCN(C(=O)OC5CCCC5)CC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 67, Step 4 starting from cyclopentyl 4-nitrophenyl carbonate and piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate HCl salt. Analytic LCMS (M+H)+: m/z=564.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C([N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])(O)=O>O1CCCC1>[C:20]1(=[O:21])[N:16]([NH:1][CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[C:17](=[O:26])[C:18]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]12
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C(O)N1C(=O)c2ccccc2C1=O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1NCCc1c[nH]c2ccccc12

Procedure:
As shown in reaction Scheme A, treatment of tryptamine (1) with N-carboxyphthalimide in an inert organic solvent such as tetrahydrofuran at a temperature of 20-65° C., preferably 65° C., for a period of 12-48 hours gives the corresponding N-phthalimidotryptamine derivative (2). The N-phthalimidotryptamine (2) could be further modified by treatment with a brominating agent such as pyridinium hydrobromide perbromide, pyrrolidone hydrotribromide, or the like in an inert organic solvent such as tetrahydrofuran, methylene chloride, chloroform, or mixtures thereof at 0-25° C. for a period of 30 minutes to 4 hours to provide the 2-bromotryptamine (3). Bromide (3) may be reacted with an arylboronic acid (prepared essentially as described in: Gronowitz, S.; Hornfeldt, A.-B.; Yang, Y.-H. Chem. Scr. 1986, 26, 311-314.) with palladium (0) catalysis, a weak base such as aqueous sodium carbonate or the like, and a chloride source such as lithium chloride in an inert solvent like toluene, benzene, ethanol, propanol or mixtures thereof at a temperature of 25°-100° C., preferably 80° C., for a period of 1-6 hours to give the 2-aryltryptamine derivative (4). Finally, the phthalimido group may be removed by treatment of (4) with aqueous hydrazine in an inert solvent such as methanol or ethanol at a temperature of 0°-25° C. for a period of 4-24 hours to give tryptamine (5).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH2:4][CH2:5][O:6][C:7]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:10][C:8]=2[CH:9]=1.[C:21]1([P:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[Br-:1].[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:7]3[O:6][CH2:5][CH2:4][C:3]([CH2:2][P+:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:9][C:8]=3[CH:10]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(CBr)CCO3)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CCO3)cc1
Product: [Br-]
Yield: 92.9 %

Procedure:
Into a solution of 4-bromomethyl-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine (329 mg) in toluene (10 ml) was added triphenylphosphine (393 mg), and the resulting mixture was refluxed for 2 hours. After gradual cooling, the precipitate was collected by filtration and was washed with toluene. The precipitate was dried under reduced pressure to obtain [7-(4-methylphenyl)-2,3-dihydro-1-benzooxepin-4-yl]methyltriphenylphosphonium bromide (549 mg) as a white powder.
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[N:6]=[N:7][C:8]([N:11]([CH3:13])[CH3:12])=[CH:9][CH:10]=1)[NH2:4].[CH3:14][C:15](=O)[CH2:16][CH2:17][C:18](=O)[CH3:19].C([O-])(=O)C.[Na+].C(OCC)C>C(O)(=O)C>[CH3:19][C:18]1[N:4]([NH:3][C:5]2[N:6]=[N:7][C:8]([N:11]([CH3:13])[CH3:12])=[CH:9][CH:10]=2)[C:15]([CH3:14])=[CH:16][CH:17]=1
Reactant: CN(C)c1ccc(NN)nn1
Reactant: CC(=O)CCC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1ccc(C)n1Nc1ccc(N(C)C)nn1
Yield: 47 %

Procedure:
The product is obtained according to the procedure of example 19 by reacting 3-hydrazino-6-dimethylamino-pyridazine dihydrochloride and 2,5-hexanedione in acetic acid in the presence of sodium acetate. Yield 47%; m.p. 165°-167° C. (from ethyl ether).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:8]=2[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[S:6]1(=[O:24])=[O:23].[CH3:25][NH2:26].Cl>>[F:15][C:12]1[CH:13]=[CH:14][C:8]2[N:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[S:6](=[O:24])(=[O:23])[N:5]([CH2:4][CH2:3][CH2:2][NH:26][CH3:25])[CH2:10][C:9]=2[CH:11]=1
Reactant: O=S1(=O)N(CCCBr)Cc2cc(F)ccc2N1c1ccccc1F
Reactant: CN
Agent: Cl
Product: CNCCCN1Cc2cc(F)ccc2N(c2ccccc2F)S1(=O)=O
Yield: 68 %

Procedure:
In an analogous manner to Example 111 step 5, 3-(3-bromopropyl)-6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.1 g, 0.25 mmol) was reacted to methylamine and then treated with HCl to provide 3-[6-fluoro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine (0.102 g, 68%) as a white solid:
Reaction SMILES: [C:1]([C:3]([O:6][N:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([CH3:14])([CH3:13])[C:9]([NH:11][CH3:12])=[O:10])([CH3:5])[CH3:4])#[N:2].N(C1(C#N)CCCCC1)=N[C:21]1(C#N)[CH2:26]CCC[CH2:22]1.Cl[C:38]1[CH:43]=CC=C[CH:39]=1>>[C:1]([C:3]1([O:6][N:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([CH3:14])([CH3:13])[C:9]([NH:11][CH2:12][CH2:39][CH2:38][CH3:43])=[O:10])[CH2:5][CH2:26][CH2:21][CH2:22][CH2:4]1)#[N:2]
Reactant: Clc1ccccc1
Reactant: CNC(=O)C(C)(C)N(OC(C)(C)C#N)C(C)(C)C
Reactant: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Product: CCCCNC(=O)C(C)(C)N(OC1(C#N)CCCCC1)C(C)(C)C
Yield: 53 %

Procedure:
The compound is prepared in analogy to compound (201) from the nitroxide (103) and azobis(cyclohexanecarbonitrile) in chlorbenzene at 100° C. in 53% yield as colorless oil.
Reaction SMILES: CCCCC.[H-].[Na+].[CH3:8][N:9]([CH3:28])[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=2)[C:13]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:12][N:11]=1.[CH:29]([N:32]=[C:33]=[O:34])([CH3:31])[CH3:30]>C1COCC1>[CH3:28][N:9]([CH3:8])[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=2)[C:13]([S:24]([NH:27][C:33]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:34])(=[O:25])=[O:26])=[CH:12][N:11]=1
Reactant: CC(C)N=C=O
Reactant: Cc1cccc(Nc2nc(N(C)C)ncc2S(N)(=O)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1cccc(Nc2nc(N(C)C)ncc2S(=O)(=O)NC(=O)NC(C)C)c1
Yield: 97.1 %

Procedure:
Pentane washed sodium hydride (22.0 mmol, 2.05 eq) was suspended in THF (100 mL) and 2-(dimethylamino)-4-[(3-methylphenyl)amino]-5-pyrimidinesulfonamide (3.72 g, 10.74 mmol) was added as a powder over a 30 minute period. After 90 minutes the solidified reaction was loosened by adding more THF (30 mL) followed by adding isopropyl isocyanate (1.09 mL, 11.06 mmole, 2.05 eq). After stirring 90 minutes a small portion of isopropyl isocyanate (150 mL) was added to complete the reaction. The THF was removed under reduced pressure and the residue was dissolved in warm water (100 mL). The pH was adjusted to 4 with acetic acid and the aqueous phase was extracted with four 150 mL portions of ethyl acetate. The organic portions were combined, dried (Na2SO4), decanted and the solvent removed to yield pale yellow crystals (4.11 g, 10.43 mmol, 97%). The crude material was crystallized once from ethanol/water to yield 3.45 g (8.76 mmol, 81%) of pure product, m.p. 178.5°-179° C.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:23][NH2:24]>CCO>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:23][NH2:24])=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: NN
Reactant: CCOC(=O)CN1CCN(C(=O)c2ccc(C#N)cc2)CC1
Solvent: CCO
Product: N#Cc1ccc(C(=O)N2CCN(CC(=O)NN)CC2)cc1
Yield: 55.8 %

Procedure:
Synthesized according to General Procedure C with modification as noted: 51e (5.59 g, 18.6 mmol, 1.0 equiv.), anhydrous hydrazine (2.4 mL, 74.4 mmol, 4.0 equiv.), EtOH (35 mL, 0.5 M). After extraction with CH2Cl2, the aqueous layer was extracted with EtOAc (3×). 46e (2.98 g, 55.8%) was obtained as an off-white solid after extraction without further purification. 1H-NMR (500 MHz, CDCl3) δ 8.02 (br s, 1H), 7.70 (d, 2H, J=8.5 Hz), 7.48 (d, 2H, J=8.5 Hz), 3.86 (br d, 2H, J=3.5 Hz), 3.78 (br s, 2H), 3.37 (br s, 2H), 3.11 (s, 2H), 2.60 (br s, 2H), 2.46 (br s, 2H). 13C-NMR (125 MHz, CDCl3) δ 169.8, 168.4, 139.8, 132.6, 127.9, 118.1, 113.8, 60.6, 53.8 (br), 53.3 (br), 47.6 (br), 42.2 (br). HRMS (ESI): 288.1464 (M+1); calcd. for C14H18N5O2: 288.1461.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11]1([CH:17]2[CH2:23][C:22](=O)O[C:19](=[O:20])[CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(C)=O>C1COCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[N:9]3[C:19](=[O:20])[CH2:18][CH:17]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:23][C:22]3=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C1CC(c2ccccc2)CC(=O)O1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=C1CC(c2ccccc2)Cc2nc3cc(Cl)c(Cl)cc3n21
Reaction time: 0.5 h
Yield: 18.7 %

Procedure:
The solution of commercial 4,5-dichloro-1,2-phenylenediamine (0.38 g) and 3-phenylglutaric anhydride (0.4 g) in THF (1 ml) was heated shortly and kept at rt for 0.5 h. The solvent was removed in vacuo and the residue redissolved in acetic acid (3 ml). The dark solution was heated to reflux overnight. Then all volatiles were removed in vacuo and the residue was heated with ethanol (5 ml). After reccoling to rt the precipitate was collected by filtration, washed with ethanol, and dried to give a crude (0.39 g). The crude was decolorized in boiling acetone solution with activated carbon and filtered over Celite. Concentration of the filtrate and drying of the residue afforded 7,8-dichloro-3-phenyl-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one (0.13 g) as colourless crystals.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[C:29]2[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:30][C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:20]=[CH:21][CH:22]=[N:23]3)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc2nccnc2c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2nccnc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available quinoxaline-6-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.68 min.; [M+H]+: 378.17 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[N:9]=[C:10]([NH2:12])[N:11]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.[Br:19][C:20]1[CH:21]=[C:22]([C:26](Cl)=[O:27])[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[C:26]([NH:12][C:10]1[N:11]=[C:7]2[C:6]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]2[N:9]=1)=[O:27]
Reactant: COc1ccc(-c2ccccc2)c2nc(N)nn12
Reactant: O=C(Cl)c1cccc(Br)c1
Product: COc1ccc(-c2ccccc2)c2nc(NC(=O)c3cccc(Br)c3)nn12

Procedure:
According to example 6, the title compound was synthesized from 5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-y-lamine and 3-bromo-phenyl carboxylic acid chloride (MS m/e (%): 423.3 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=[O:9])[CH:3]=1.FC(F)(F)C(O)=O.NC1C(C2C=CC(CC(N)=O)=CC=2)=C(OC2C=CC(NC(NC(=O)CC3C=CC(F)=CC=3)=O)=CC=2F)C=CN=1.[NH2:57][C:58]1[CH:63]=[C:62]([F:64])[C:61]([OH:65])=[C:60]([F:66])[CH:59]=1>>[NH2:57][C:58]1[CH:63]=[C:62]([F:64])[C:61]([O:65][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=[O:9])[CH:3]=2)=[C:60]([F:66])[CH:59]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1cc(F)c(O)c(F)c1
Agent: NC(=O)Cc1ccc(-c2c(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ccnc2N)cc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cc(Oc2c(F)cc(N)cc2F)ccn1
Yield: 28.9 %

Procedure:
4-Chloropicolinamide (0.47 g, 3.0 mmol) was converted to the title compound (0.23 g, 29%) in a manner similar to the preparation of Compound C of Example 112, except that 4-amino-2,6-difluorophenol (0.44 g, 3.0 mmol) was used instead of 4-amino-2,5-difluorophenol. 1H NMR (DMSO-d6) δ 8.60 (d, 1H, J=5.6 Hz), 8.22 (br s, 1H), 7.83 (br s, 1H), 7.45-7.46 (m, 1H), 7.30-7.32 (m, 1H), 6.43-6.49 (m, 2H), 5.94 (s, 2H); MS (ESI+) m/z 266 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22].Cl.[NH2:30][OH:31]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[N:30][OH:31])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(OCC)OCC
Reactant: O=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(Cc1ccc(OCc2ccccc2)cc1)=NO
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.1 %

Procedure:
To a solution of 4-benzyloxyphenylacetyl chloride (4.0 g, 16.2 mmol) in THF (10.0 mL) at room temperature was slowly added triethyl phosphite (3.33 mL, 19.5 mmol). The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was treated with hexanes (20 mL) and the mixture was filtered. White solid was collected and air-dried. The solid was dissolved in pyridine (25.0 mL) and hydroxylamine hydrochloride (1.96 g, 28 mmol) was added. The reaction mixture was stirred at room temperature for 72 h and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (7:3) to afford diethyl 2-(4-benzyloxyphenyl)-1-(hydroxyimino)ethylphosphonate as a colorless oil (5.2 g, 85%): 1H NMR (300 MHz, CDCl3): δ 7.18-7.38 (m, 7 H), 6.80 (d, J=6.2 Hz, 2 H), 4.94 (s, 2 H), 3.80-4.10 (m, 4 H), 3.80 (s, 1 H), 3.76 (s, 1 H), 1.16 (t, J=6.0 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-ethyl acetate (2:3); Rf=0.55.