Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=CC=1.P(=O)(O)(O)O.C1CC=CC=1>C(C(C)=O)C(C)C.O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH:10]2[CH2:15][CH2:14][CH:13]=[CH:16]2)[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: Cc1cccc(C)c1O
Reactant: Cc1ccccc1
Agent: C1=CCC=C1
Agent: O=P(O)(O)O
Solvent: CC(=O)CC(C)C
Solvent: C1CCOC1
Product: Cc1cc(C2C=CCC2)cc(C)c1O

Procedure:
Into a 2-liter flask having a stirrer, a condenser and a thermometer, 366 g of 2,6-dimethylphenol, 360 g of toluene and 102 g of phosphoric acid were introduced, and a solution of mixture of 247 g of cyclopentadiene and 200 g of toluene was added dropwise over a period of 3 hours while stirring the mixture under ice cooling, followed by further stirring for 4 hours at room temperature. To the reaction solution thus obtained, tetrahydrofuran (hereinafter “THF”) and methyl isobutyl ketone (hereinafter “MIBK”) were added, and the resultant solution was washed with water until it turned neutral, followed by distillation under reduced pressure. After the reaction solvent had evaporated, unreacted 2,6-dimethylphenol evaporated. A fraction at 3 mmHg and 140° C. was 2,6-dimethyl-4-(2-cyclopenten-1-yl)phenol. The results of analysis by GPC thereof are shown in FIG. 1. Its yield determined by GPC was 94% (area ratio).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:10]1([S:16][C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1cccc(I)c1
Reactant: Sc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: N#Cc1cccc(Sc2ccccc2)c1
Yield: 85.7 %

Procedure:
The general procedure in example 39 was followed. 3-Iodobenzonitrile (229 mg, 1.0 mmol), thiophenol (103 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 3-cyanophenyl phenyl sulfide (181 mg, 86% yield) as colorless liquid. Column chromatography solvent (hexane/ethyl acetate=25/1). Rf=0.4 (hexane/ethyl acetate=20/1). 1H NM (CDCl3, 300 MHz) δ 7.30-7.45 (m, 9 H). 13C NMR(CDCl3,75MHz) δ 140.2, 133.6, 132.9, 132.3, 131.7, 130.0, 129.7, 129.6, 129.1, 118.5, 113.5. MS (EI) m/z (relative intensity) 211 (30), 185 (20), 134 (100).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:33])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[N:30][CH:29]=[CH:28][N:27]=4)[CH:21]=3)[CH2:18][C:17](=[O:33])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3cnccn3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-methyl-2-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M79) (0.31 g, 0.64 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (208 mg, 89%).
Reaction SMILES: [C:1]([CH2:4][C@@H:5]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([OH:3])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[F:38][C:39]([F:48])([F:47])[CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C(Cl)Cl>[CH2:16]([C@H:5]([CH2:4][C:1]([N:44]1[CH2:43][CH2:42][N:41]([CH2:40][C:39]([F:47])([F:48])[F:38])[CH2:46][CH2:45]1)=[O:3])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: FC(F)(F)CN1CCNCC1
Reactant: O=C(O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H](CC(=O)N1CCN(CC(F)(F)F)CC1)Cc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
The resultant acid from Example 23 (0.500 g, 1.68 mmol) in CH2Cl2 (7 ml) at -10° C. was treated with N-methylmorpholine (0.20 ml, 1.82 mmol) and then isobutyl chloroformate (0.22 ml, 1.68 mmol). After 5 min 1-trifluoroethylpiperazine (0.30 g, 1.78 mmol) was added and the mixture was stirred at -10° C. for 15 min and then at room temperature for 2 h. The solvent was evaporated and the residue was taken up in ethyl acetate which was washed with saturated NaHCO3 solution, water and brine, and then dried over Na2SO4 and evaporated. Chromatography of the residue on silica gel with 20-33% ethyl acetate in hexane provided 0.61 g (81%) of an oil. 1H NMR (CDCl3) δ7.10-7.40 (m,10H), 5.15 (d,1H), 5.05 (d,1H), 3.25-3.70 (m,5H), 3.04 (dd,1H), 2.97 (q,2H), 2.81 (dd,1H), 2.72 (dd,1H), 2.60 (m,4H), 2.32 (dd,1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][CH2:13][C:14]1[NH:15][CH:16]=[CH:17][N:18]=1)(=[O:10])=[O:9].[C:19]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27])([CH3:22])([CH3:21])[CH3:20].[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34]>CO.C(OCC)(=O)C>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[NH:18]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:13][CH2:12][NH:11][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([C:19]([CH3:21])([CH3:20])[CH3:22])[CH:24]=1)(=[O:10])=[O:9]
Reactant: Nc1ccccc1S(=O)(=O)NCCc1ncc[nH]1
Reactant: CC(C)(C)c1cccc(C(=O)Cl)c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)c1cccc(C(=O)Nc2ccccc2S(=O)(=O)NCCc2ncc[nH]2)c1
Yield: 84.2 %

Procedure:
The titled compound was prepared substantially in accordance with the method detailed in Example 1C using 2.80 g (0.0107 mol) of 2-amino-N-[2-(1H-imidazol-2-yl)-ethyl] benzene sulfonamide and 4.20 g (0.0213 mol) of meta-t-butylbenzoyl chloride with the exception that, after reducing the reaction solution to dryness under reduced pressure the resultant residue was dissolved in methanol. The resulting solution was heated to reflux for approximately one hour and then reduced to dryness under reduced pressure. The resultant residue was redissolved in an ethyl acetate/aqueous sodium bicarbonate mixture. The resulting layers were separated and the organic layer was washed with water and then a saturated sodium chloride solution, dried over anhydrous sodium sulfate and then reduced to dryness under reduced pressure. The resultant residue was purified using preparatory high performance liquid chromatography (8000 ml of a gradient of methylene chloride to 10% methanol and 0.5% ammonium hydroxide in methylene chloride). Fractions containing the free base form of the desired titled compound were combined and then reduced to dryness under reduced pressure to provide an oil. This oil was dissolved in methanol and 0.36 g of oxalic acid were added, with stirring. The resulting solution was reduced to dryness under reduced pressure to provide a foam. This foam was crystallized from a 1:10 solution of methanol/ethyl acetate to provide 1.74 g of the desired titled compound (m.p. 191°-193.5° C.).
Reaction SMILES: [C:1]1([N:7]([C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([N:41]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:42]3[CH:43]=[C:44]([CH3:48])[CH:45]=[CH:46][CH:47]=3)=[CH:37][CH:36]=2)=[CH:31][CH:30]=1.N1[C:68]2[C:59](=[CH:60][CH:61]=[C:62]3[C:67]=2[N:66]=[CH:65][CH:64]=[CH:63]3)[CH:58]=CC=1.[OH-].[K+]>C1(C)C(C)=CC=CC=1>[C:1]1([N:7]([C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:20]=[CH:19][C:17]([N:18]([C:17]4[CH:19]=[CH:20][C:14]([C:11]5[CH:12]=[CH:13][C:8]([N:66]([C:67]6[CH:68]=[C:59]([CH3:58])[CH:60]=[CH:61][CH:62]=6)[C:65]6[CH:64]=[CH:63][CH:6]=[CH:1][CH:2]=6)=[CH:9][CH:10]=5)=[CH:15][CH:16]=4)[C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:40]=[CH:39][C:38]([N:41]([C:42]6[CH:43]=[C:44]([CH3:48])[CH:45]=[CH:46][CH:47]=6)[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[CH:37][CH:36]=5)=[CH:31][CH:30]=4)=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: Cc1cccc(N(c2ccccc2)c2ccc(-c3ccc(I)cc3)cc2)c1
Reactant: Cc1cccc(N(c2ccccc2)c2ccc(-c3ccc(N)cc3)cc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: Cc1cccc(N(c2ccccc2)c2ccc(-c3ccc(N(c4ccc(-c5ccc(N(c6ccccc6)c6cccc(C)c6)cc5)cc4)c4ccc(-c5ccc(N(c6ccccc6)c6cccc(C)c6)cc5)cc4)cc3)cc2)c1
Reaction time: 6 h

Procedure:
A 250 milliliter 3-necked round bottom flask equipped with a mechanical stirrer, reflux condenser, and argon inlet was purged with argon and then charged with N-phenyl-N-m-tolyl benzidine (8.0 grams, 0.023 mol), 4'-iodo-N-phenyl-N-m-tolyl-4-aminobiphenyl (17.5 grams, 0.038 mol), xylene (15 milliliters), 1,10-phenanthroline (0.34 gram, 1.9 mmol), cuprous chloride (0.188 gram, 1.9 mmol), and potassium hydroxide flakes (17.06 grams, 0.3 mol). Under an argon atmosphere, the reaction mixture was heated to reflux with an oil bath and allowed to proceed at that temperature until chromatographic analysis indicated that the reaction was complete after approximately 6 hours. The oil bath was removed and 100 milliliters of toluene and 25 milliliters of water were then added with efficient stirring. The resulting two phase mixture was transferred into a separatory funnel and the layers separated. The organic phase was washed with water and treated under argon with 25 grams of alumina. After the alumina was filtered off, the organic phase was evaporated to remove most of the toluene. The above product, Compound (1), was obtained by recrystallization of the residue from cyclohexane. Yield: 12.3 grams; m.p. 234.28° C.; Tg 134° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].[C:24](=[O:27])([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][N:11]([CH2:7][CH:6]3[CH2:5][CH2:13][CH2:12][CH2:24][O:27]3)[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2c(ncn2CC2CCCCO2)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 60 °C
Reaction time: 12 h

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8b (0.25 g, 0.63 mmol) is dissolved in N,N-dimethylformamide (5 mL). 2-Brothomethyl-tetrahydro-pyran (0.34 g, 1.88 mmol) and potassium carbonate (0.26 g, 1.88 mmol) are added and the reaction mixture is stirred at 60° C. for 12 hours under N2. The reaction mixture is poured into a separatory funnel, diluted with ethyl acetate and water and the layers separated. The ethyl acetate layer is washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. The resulting solid residue is triturated with diethyl ether to yield a pale yellow solid (N3 regioisomer by NMR) and a yellow filtrate (mixture of N1 and N3 regioisomers by NMR). The solids are collected and washed with diethyl ether to yield 0.12 g (37%) of the pure desired N3 regioisomeric product as a pale yellow solid. MS ESI (+) m/z 496, 498 (M+, Br pattern) detected.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][C:6]([CH3:24])([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH2:23])[CH2:13][CH2:12]1)=[O:10])[CH3:7].[CH3:25][C:26]([CH3:28])=O.C(O)(=O)C>CO.[OH-].[Na+].ClCCl>[CH3:7][C:6]([CH3:24])([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[N:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH:23][CH:26]([CH3:28])[CH3:25])[CH2:15][CH2:16]1)=[O:10])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncncc2N)CC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)Nc1cncnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 72 h

Procedure:
A solution of sodium cyanoborohydride (0.13 g) in methanol (4 ml) is added to a mixture of 1-[1,1-dimethylethoxycarbonyl]-4-[5-amino-6-pyrimidinyl]piperazine (PREPARATION 28, 0.44 g), acetone (3 ml), and glacial acetic acid (0.4 ml) in methanol (7 ml) at 0°. The mixture is stirred at 20°-25° for 72 h. The reaction is diluted with an aqueous sodium hydroxide solution (10%) and dichloromethane. The phases are separated and the organic phase is washed with water and the concentrated to a colorless liquid which is flash chromatographed on silica gel eluting with methanol/chloroform (1/99). The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 1.26, 1.49, 3.2, 3.44, 3.5-3.62, 7.89 and 8.33 δ.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][C:26]1[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([F:24])=[C:2]([NH:1][C:32]([C:27]5[C:26]([CH3:25])=[CH:31][CH:30]=[CH:29][N:28]=5)=[O:33])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1cccnc1C(=O)O
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccnc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 46.9 %

Procedure:
Using N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.611 mmol), 3-methylpyridine-2-carboxylic acid (126 mg, 0.917 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (187 mg, 0.978 mmol), 1-hydroxybenzotriazole (133 mg, 0.988 mmol), triethylamine (0.14 mL, 1.039 mmol) and N,N-dimethylformamide (6.0 mL), and by a reaction in the same manner as in Example 187, the title compound (128 mg, 47%) was obtained as colorless crystals.
Reaction SMILES: O.[NH2:2][NH2:3].C(O)C.[F:7][C:8]([F:15])([CH3:14])[C:9](OCC)=O.C(S[C:19]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C>C(O)CCC>[F:15][C:8]([C:9]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:3][N:2]=1)([F:7])[CH3:14]
Reactant: CCSC(=Nc1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(C)(F)F
Reactant: NN
Solvent: CCO
Solvent: CCCCO
Solvent: O
Product: CC(F)(F)c1nnc(-c2ccccc2)n1-c1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 27 %

Procedure:
Next, 0.54 g (11 mmol) of hydrazine monohydrate and 10 mL of ethanol were put in a 100 mL three-neck flask and stirred at −10° C. for 15 minutes. Then, 1.5 g (11 mmol) of ethyl 2,2-difluoropropionate was dripped to this mixed solution at −10° C. little by little, and the solution was stirred for 48 hours while the temperature was increased to room temperature. Then, 2.6 g (11 mmol) of N-[(ethylsulfanyl)phenylmethylidene]aniline prepared in Step 1 and 20 mL of 1-butanol were added to this mixed solution, and the mixed solution was refluxed at 110° C. for 8 hours. After the reflux, the solvent was distilled off under a reduced pressure to give an oily substance. The given oily substance was purified by silica gel column chromatography. As developing solvents, first, toluene was used, and then ethyl acetate was used. The obtained fraction was concentrated to give a solid. This solid was recrystallized from a mixed solvent of ethanol and hexane, so that 3-(1,1-difluoroethyl)-4,5-diphenyl-4H-1,2,4-triazole (abbreviation: HMCF2ptz) was prepared (a white solid, yield: 27%). The synthesis scheme of Step 2 is shown by (b-1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=O)[CH2:6]1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+].CO>O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=[N:19][OH:20])[CH2:6]1
Reactant: COC(=O)CC1CC(=O)c2ccc(OC)cc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CC1CC(=NO)c2ccc(OC)cc21
Temperature: 25 °C

Procedure:
(6-Methoxy-3-oxo-indan-1-yl)-acetic acid methyl ester (12.0 g), hydroxylamine hydrochloride (4.6 g), and sodium acetate (5.5 g) dissolved in water (40 mL) and methanol (50 mL) are stirred at reflux temperature for 3 h. After cooling to room temperature, water (100 mL) is added and the solution is extracted with ethyl acetate. The combined organic extracts are washed with water and brine and dried (MgSO4). The solvent is evaporated to give the product as a brown oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17]([N:19]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:20]3=[O:30])=[O:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][NH:42][CH:43]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:41]1[CH:40]=[C:39]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:16][C:17]([N:19]4[CH2:23][CH2:22][N:21]([CH:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)[C:20]4=[O:30])=[O:18])=[N:13][C:14]=3[CH3:15])[CH:5]=[CH:4][N:3]=2)[CH:43]=[N:42]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Cc1nc(NC(=O)N2CCN(C3CCOCC3)C2=O)ccc1Oc1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(NC(=O)N2CCN(C3CCOCC3)C2=O)ccc1Oc1ccnc(-c2cn[nH]c2)c1
Temperature: 25 °C
Yield: 55.5 %

Procedure:
A solution of Example C3 (0.12 g, 0.28 mmol) in dioxane (4 mL) was sparged with Ar, treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.08 g, 0.42 mmol), a solution of K2CO3 (0.077 g, 0.55 mmol) in water (1 mL) and Pd(PPh3)4 (0.032 g, 0.03 mmol) and heated at 90° C. overnight. The mixture was cooled to RT, diluted with water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (72 mg, 56%). 1H NMR (400 MHz, DMSO-d6): δ 13.05 (br s, 1 H), 10.89 (s, 1 H), 8.35 (d, J=5.7 Hz, 1 H), 8.31 (brs, 1 H), 8.03 (s, 1 H), 7.89 (d, J=8.8 Hz, 1 H), 7.61 (d, J=8.8 Hz, 1 H), 7.28 (d, J=2.4 Hz, 1 H), 6.56 (dd, J=5.7, 2.4 Hz, 1 H), 3.95-3.77 (m, 5 H), 3.43-3.39 (m, 4 H), 2.24 (s, 3 H), 1.71-1.70 (m, 2 H), 1.60 (d, J=12.4 Hz, 2 H); MS (ESI) m/z: 464.2 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[CH2:5][N:4]1[C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[N:24]=[CH:23][CH:22]=[N:21]1)=[O:12].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:29]=2[N:30]=1>>[Cl:35][C:32]1[CH:33]=[CH:34][C:28]2[O:27][C:26]([NH:1][CH2:2][CH:3]3[CH:7]4[CH2:8][CH2:9][CH2:10][CH:6]4[CH2:5][N:4]3[C:11]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=3[N:20]3[N:24]=[CH:23][CH:22]=[N:21]3)=[O:12])=[N:30][C:29]=2[CH:31]=1
Reactant: Clc1ccc2oc(Cl)nc2c1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CCCC3C2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CCCC3C2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A2 using (1-(aminomethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2,5-dichlorobenzoxazole. MS (ESI) 477 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:8]([NH2:17])[N:7]=[C:6]([NH2:18])[N:5]=1)=O.C(O)C.Cl.[NH2:23][OH:24].C([O-])(=O)C.[Na+]>O>[CH3:1][C:2](=[N:23][OH:24])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:8]([NH2:17])[N:7]=[C:6]([NH2:18])[N:5]=1
Reactant: CC(=O)c1nc(N)nc(N)c1-c1ccc(Cl)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1nc(N)nc(N)c1-c1ccc(Cl)cc1

Procedure:
[2,6-Diamino-5-(p-chlorophenyl)-4-pyrimidinyl] methyl ketone (2.6 g.) was dissolved in 30 ml. of ethanol and hydroxylamine, hydrochloride (1.5 g.) and sodium acetate (2.5 g.) in 25 ml. of water was added and the mixture refluxed for 5 hours. After cooling a white precipitate separated; it was recrystallized from methanol to give 1.5 g. of the title product, m.p. 256°-259°.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH3:13])[O:8][CH:7]([C:18]([F:21])([F:20])[F:19])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2.[CH3:27]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Cs+].[Cs+].O>COCCOCCOC>[CH2:14]([N:12]([CH3:13])[C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8]2)=[CH:3][C:2]=1[CH3:27])[CH:15]([CH3:17])[CH3:16]
Reactant: CB1OB(C)OB(C)O1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(N(C)CC(C)C)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOCCOC
Solvent: O
Product: CCOC(=O)C1=Cc2cc(C)c(N(C)CC(C)C)cc2OC1C(F)(F)F
Temperature: 115 °C
Yield: 45 %

Procedure:
A mixture of ethyl 6-chloro-7-[isobutyl(methyl)amino]-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 8c (0.50 g, 1.28 mmole), trimethylboroxine (0.38 g, 2.75 mmole), [(tBu3P)PdBr]2 (0.01 g), and Cs2CO3 (0.75 g, 2.31 mmole) in anhydrous diglyme (10.0 mL) was heated to 115° C. under a dry N2 atmosphere for 18 hrs. The contents were poured into water (40 ml) and extracted with EtOAc (2×40 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil which was subject to HPLC (reverse phase) and eluted with 50-85% ACN/water with 0.05% TFA to give yellow solid (0.21 g, 45%). No further purification was performed. GCMS m/z 371.0 (M+). LCMS m/z 372.0 (M+H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:35]([CH2:37][C:38]([N:40]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:41]1[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=1)=[O:39])[CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]([CH2:37][C:38]([N:40]([C:41]1[CH:42]=[CH:43][C:44]([NH:47]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:45][CH:46]=1)[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:39])[CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CN(CC(=O)N(Cc1ccccc1)c1ccc(N)cc1)Cc1ccccc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(Cc2ccccc2)C(=O)CN(C)Cc2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-((N-benzyl-N-methyl-amino)-methylcarbonyl)-N-benzyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C40H36N4O4