Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=[O:13].[N:20]1(C(=N)N2C=CN=C2)C=CN=[CH:21]1>CS(C)=O>[NH2:20][C:21]1[O:13][C:12]([C:11]2[CH:16]=[CH:17][N:18]=[CH:19][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[N:14][N:15]=1
Reactant: NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Reactant: N=C(n1ccnc1)n1ccnc1
Solvent: CS(C)=O
Product: Nc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid hydrazide (1 g, 2.68 mmol) in DMSO (6 mL) were added 1,1-di-1H-imidazol-1-yl-methyleneamine (864 mg, 5.36 mmol). The reaction mixture was stirred at RT for 18 h. Quenching of the reaction by adding water (60 mL). A solid precipitated out. The solid was filtered, washed with water and cold methanol. Yield: white solid 1.0 g. LC-MS (Method A) [4.66 min; 398(M+1)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:23][CH2:22][O:21][CH:20]2[CH3:24])[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:7]=1.Cl.[NH2:28][OH:29]>>[F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:23][CH2:22][O:21][CH:20]2[CH3:24])[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[N:28][OH:29])[CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: NO
Reactant: CCC(=O)c1ccc(Sc2cc(F)cc(C3(OC)CCOC3C)c2)cc1
Agent: Cl
Product: CCC(=NO)c1ccc(Sc2cc(F)cc(C3(OC)CCOC3C)c2)cc1
Yield: 15 %

Procedure:
Using an analogous procedure that described in Example 66, 4'-{5-fluoro-3-[(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]phenylthio}propiophenone was reacted with hydroxylamine hydrochloride to give 4'-{5-fluoro-3-[(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]phenylthio}propiophenone oxime in 15% yield, m.p. 113°-114° C.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:13]([C:16]1[CH:17]=[C:18]([N:22]=[C:23]=[O:24])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>CCO>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1)=[O:24])([CH3:5])([CH3:6])[CH3:7]
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCNC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.35 g (19.2 mmol) of N-boc-1,3-diaminopropane in 50 ml of EtOH is mixed at 0° C. in portions with 3.15 g (19.2 mmol) of 3-nitrophenyl isocyanate. The batch is stirred overnight at room temperature and then concentrated by evaporation in a rotary evaporator. It is mixed with DCM and washed with water. The organic phase is filtered through a Whatman filter and concentrated by evaporation. 6.4 g (18.9 mmol, corresponding to 98% of theory) of the product is obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH3:13][C@@H:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:15]1([C@H:14]([N:21]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([F:12])([F:11])[F:1])[CH3:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](N=C(c1ccccc1)C(F)(F)F)c1ccccc1
Yield: 100.1 %

Procedure:
A solution of 2,2,2-trifluoroacetophenone (7.0 g, 40 mmol), R-(+)-α-methylbenzylamine (7.75 mL, 60 mmol), and p-toluenesulfonic acid monohydrate (0.77g, 4.0 mmol) in toluene (40 mL) was refluxed for 18 hours with a Dean-Stark trap. After cooling, the reaction mixture was diluted with toluene (50 mL), washed with 5% NaOH (1×50 mL), saturated NH4Cl (4×30 mL) and brine, dried over MgSO4, concentrated and dried at room temperature in vacuum to give the title compound as pale yellow liquid (11.1 g).
Reaction SMILES: [BH4-].[Li+].[CH2:3]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[I:19])[C:12](OC)=[O:13])[CH3:4].Cl>O1CCCC1>[CH2:3]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH2:12][OH:13])[CH:16]=[CH:17][C:18]=1[I:19])[CH3:4]
Reactant: CCOCCOc1cc(C(=O)OC)ccc1I
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOCCOc1cc(CO)ccc1I
Temperature: 60 °C
Yield: 93.6 %

Procedure:
1.2 g (55 mmol) of lithium borohydride are added to a solution of 5.93 g (18 mmol) of methyl 3-(2-ethoxyethoxy)-4-iodobenzoate in 30 mL of tetrahydrofuran. The reaction mixture is heated at 60° C. overnight and then hydrolyzed in ice-cold saturated ammonium chloride solution. The reaction medium is neutralized with concentrated hydrochloric acid and then extracted with ethyl acetate. The organic phases are washed with water and dried over sodium sulfate. The solvent is evaporated off and 5.43 g (99%) of [3-(2-ethoxyethoxy)-4-iodophenyl]methanol are obtained in the form of a colorless oil.
Reaction SMILES: [N:1]1([C:10]2[N:15]=[C:14]3[N:16]([CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)C(=O)[NH:18][C:13]3=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.N1(C2N=C3N(CC4C=NC=CC=4)C=NC3=CC=2)C2C=CC=CC=2N=C1.N1(C2N=C(NCC3C=NC=CC=3)C([N+]([O-])=O)=CC=2)C2C=CC=CC=2N=C1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CS(C)=O.O.C(OCC)(=O)C>[N:1]1([C:10]2[N:15]=[C:14]([NH:16][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[C:13]([NH2:18])=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=c1[nH]c2ccc(-n3cnc4ccccc43)nc2n1Cc1cccnc1
Agent: O=S([O-])S(=O)[O-]
Agent: O=[N+]([O-])c1ccc(-n2cnc3ccccc32)nc1NCc1cccnc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Nc1ccc(-n2cnc3ccccc32)nc1NCc1cccnc1
Reaction time: 2 h

Procedure:
5-(1H-Benzo[d]imidazol-1-yl)-3-(pyridin-3-ylmethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (50) and 5-(1H-benzo[d]imidazol-1-yl)-3-(pyridin-3-ylmethyl)-3H-imidazo[4,5-b]pyridine (51). A solution of 6-(1H-benzo[d]imidazol-1-yl)-3-nitro-N-(pyridin-3-ylmethyl)pyridin-2-amine (48) (50 mg) in 1 mL of DMSO was treated with a solution of Na2S2O4 (300 mg) in 1 mL of water. The mixture was stirred for two hours and diluted with 50 mL of ethyl acetate. The mixture was washed three times with 50 mL aliquots of saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo to provide the intermediate 6-(1H-benzo[d]imidazol-1-yl)-N2-(pyridin-3-ylmethyl)pyridine-2,3-diamine (49). Half of the intermediate was dissolved in methylene chloride (2 mL) and treated with 1,1′-carbonyldiimidazole (46 mg) at RT for 16 h. The resulting crude mixture was purified by preparative TLC (1000 microns, 5% MeOH/CH2Cl2) to provide 7.1 mg of 5-(1H-benzo[d]imidazol-1-yl)-3-(pyridin-3-ylmethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (50): 1H-NMR (CDCl3) δ 10.0 (br s, 1H), 8.9 (s, 1H), 8.6 (d, 1H), 8.5 (s, 1H), 7.9 (m, 2H), 7.8 (m, 1H), 7.6 (d, 1H), 7.4 (m, 2H), 7.4 (m, 1H), 7.3 (d, 1H), 5.2 (s, 2H). The other half of the reduced intermediate was dissolved in 1 mL of formic acid and heated in a microwave at 220° C. for 10 minutes. The mixture was concentrated in vacuo, diluted with methylene chloride, and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried with sodium sulfate, filtered, and concentrated in vacuo.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23]([NH:25][O:26]C4CCCCO4)=[O:24])[CH:19]=3)[CH2:14]2)=[O:12])=[CH:2]1.[ClH:33]>CO.O>[ClH:33].[OH:26][NH:25][C:23]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([C:11](=[O:12])[CH2:10][C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=1)[CH2:22][CH2:21]2)=[O:24]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)Cc1c[nH]c3ccccc13)C2
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C(NO)c1ccc2c(c1)CCN(C(=O)Cc1c[nH]c3ccccc13)C2
Reaction time: 8 h
Yield: 63 %

Procedure:
180 mg 2-(1H-indol-3-ylacetyl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide are dissolved in methanol and 6 ml of a solution of 0.1 M HCl in water are added drop wise. The mixture is stirred overnight. The mixture is evaporated in vacuo and the residue is treated with a mixture of water and acetonitrile and lyophilized. 92 mg (63%) of the title compound are obtained. MH+=350.0
Reaction SMILES: ClC1C=CC(OS([N:10]=C=O)(=O)=O)=CC=1.[O:15]=[C:16]1[C:21]2[CH:22]=[C:23]3[C:28](=[C:29]([CH2:30][CH2:31][CH3:32])[C:20]=2[O:19][C:18]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:17]1)[NH:27][C:26]([C:33]([O:35][CH3:36])=[O:34])=[CH:25][C:24]3=O.Cl>C(#N)C>[NH2:10][C:24]1[C:23]2[C:28](=[C:29]([CH2:30][CH2:31][CH3:32])[C:20]3[O:19][C:18]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:17][C:16](=[O:15])[C:21]=3[CH:22]=2)[N:27]=[C:26]([C:33]([O:35][CH3:36])=[O:34])[CH:25]=1
Reactant: O=C=NS(=O)(=O)Oc1ccc(Cl)cc1
Reactant: CCCc1c2[nH]c(C(=O)OC)cc(=O)c2cc2c(=O)cc(C(=O)OCC)oc12
Agent: Cl
Solvent: CC#N
Product: CCCc1c2nc(C(=O)OC)cc(N)c2cc2c(=O)cc(C(=O)OCC)oc12

Procedure:
4-Chlorophenoxysulphonylisocyanate (0.2 ml, 290 mg) was added to a suspension of ethyl 6,9-dihydro-4,6-dioxo-8-methoxycarbonyl-10-propyl-4H-pyrano[3,2-g]quinoline-2-carboxylate (385 mg, 1 mmol) in acetonitrile (5 ml), and then refluxed for 0.5 h. The solution was allowed to cool, ethanolic hydrogen chloride solution (2 ml) was added, and after 5 minutes the pale yellow solution was poured into aqueous ammonial solution (0.88 specific gravity, 5 ml) at 5° C., to give a thick orange precipitate. Filtration and washing with ethanol (10 ml) gave the title compound, 320 mg (83%) as an orange powder, mp 268°-270° C. (decomposes).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([CH2:12][CH2:13][NH:14][C:15](=O)[CH3:16])[CH:11]=[CH:10][CH:9]=[CH:8]1.O.[OH-].[Na+]>C(OCC)C.O1CCCC1>[CH2:15]([NH:14][CH2:13][CH2:12][N:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1)[CH3:16]
Reactant: CC(=O)NCCn1cccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCNCCn1cccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of lithium aluminum hydride (10 g) in dry diethyl ether (500 ml) is added dropwise a solution of N-[2-(1H-pyrrol-1-yl)ethyl]acetamide (10 g, described in Example 1) in dry tetrahydrofuran (250 ml). The mixture is refluxed for 3 hr, stirred overnight at room temperature, and decomposed with 10 ml of water, 10 ml of 15% sodium hydroxide, and 30 ml of water. The resultant slurry is stirred for 90 min and filtered. The filtrate is dried over magnesium chloride and evaporated to give the title compound as an oil: bp 70° C./8 mm Hg and nmr(CDCl3) δ 1.06(t), 1.64(s), 2.65(q), 2.95(t), 4.03(t), 6.19(t) and 6.70(t).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:21])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[Cl:1][C:2]1[C:3](=[O:21])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([S:23]([CH3:22])(=[O:25])=[O:24])[CH2:12][CH2:13]1
Reactant: CS(=O)(=O)Cl
Reactant: O=c1c(Cl)c(N2CCNCC2)cnn1-c1ccc(Cl)cc1
Product: CS(=O)(=O)N1CCN(c2cnn(-c3ccc(Cl)cc3)c(=O)c2Cl)CC1

Procedure:
Obtainable by general method 4 from 10.0 g (30.75 mmol) of the compound from Example 2A with 3.6 ml (46.1 mmol) of methanesulfonyl chloride.
Reaction SMILES: C1([C@@H](N[C:10](=[O:19])[CH2:11][C@H:12]([CH2:17][OH:18])[CH2:13][CH2:14][CH2:15][CH3:16])C)C=CC=CC=1>OS(O)(=O)=O.O1CCOCC1>[CH2:13]([C@H:12]1[CH2:17][O:18][C:10](=[O:19])[CH2:11]1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCC[C@@H](CO)CC(=O)N[C@@H](C)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CCCC[C@H]1COC(=O)C1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
(R)-3-Hydroxymethylheptanoic acid, (S)-1-phenylethylamide (8.4 g, 31.9 mmol) was dissolved in 1 M H2SO4/dioxane (1:1, 110 mL) and the resulting solution was refluxed overnight under argon. After cooling to rt, the reaction mixture was diluted with ethyl acetate/hexanes (1:3, 200 mL) and washed with water (2×100 mL), saturated aq. NaHCO3 (2×100 mL), and brine (100 mL). The solution was dried (Na2SO4), filtered, and concentrated to afford pure (R)-4-butyldihydrofuran-2-one as a colorless oil (3.5 g, 78%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:13])[CH2:10][CH2:11][CH3:12].CO>C1(C)C=CC=CC=1>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:9](=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCC(=O)Cl
Reactant: Cc1ccccc1N
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCC(=O)Nc1ccccc1C
Temperature: 90 °C
Yield: 89.3 %

Procedure:
1128.6 g of o-toluidine were initially charged in 500 ml of toluene and heated to 90° C. 134.3 g of butyryl chloride were added dropwise within 2 hours. After completed addition, the mixture was heated to reflux and stirring continued at this temperature until the end of gas formation. The mixture was cooled to 70° C., 12 ml of methanol were added and stirring was continued for an hour. To remove the methanol, the mixture was heated and 70 ml were distilled off. 300 ml of toluene were then distilled off and 400 ml of cyclohexane were added. The mixture was cooled to 10° C. and filtration gave 199.5 g (92% yield) of the product in 98% purity after drying.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[C:15]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=O)(=[O:17])[CH3:16].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH:21]1[CH2:22][CH2:23][N:18]([C:15](=[O:17])[CH3:16])[CH2:19][CH2:20]1
Reactant: CC(=O)N1CCCCC1=O
Reactant: Nc1ccccc1Sc1ncccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)N1CCC(Nc2ccccc2Sc2ncccn2)CC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 22.3 %

Procedure:
A solution of 2-(pyrimidin-2-ylsulfanyl)-phenylamine (AMR01106, 100 mg, 0.492 mmol), 1-acetylpiperidone (69.5 mg, 0.492 mmol) and acetic acid (0.15 mL, 2.46 mmol) in DCE (2 mL) was treated with NaBH(OAc)3 (261 mg, 1.23 mmol) and stirred under microwave irradiation for 15 min at 100° C. The reaction mixture was diluted with DCM (10 mL) and quenched with saturated NaHCO3 solution. The aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using AcOEt/MeOH 98:2 as eluent gave 1-{4-[2-(pyrimidin-2-ylsulfanyl)-phenylamino]-piperidin-1-yl}-ethanone 36 mg, 22%) as a colorless oil. 1H NMR (270 MHz, CDCl3) δ 1.20-1.40 (2H, m, CH2), 1.90-2.10 (2H, m, CH2), 2.05 (3H, s, CH3), 2.89 (1H, m, ½CH2), 3.18 (1H, m, ½CH2), 3.54-3.74 (2H, m, CH2), 4.26 (1H, m, CH), 4.75 (1H, br s, NH), 6.69-6.75 (2H, m, ArH), 6.97 (1H, t, J=4.7 Hz, Pyrimidine-H), 7.33 (1H, m, ArH), 7.49 (1H, dd, J=7.4, 1.7 Hz, ArH) and 8.47 (2H, d, J=4.7 Hz, Pyrimidine-H), 13C NMR (270 MHz, CDCl3) δ 21.57 (CH3), 31.74, 32.56, 40.14, 45.00 (CH2), 49.63 (CH), 111.45, 111.57, 117.35, 132.12, 138.13, 148.49, 157.88 (ArC and Pyridine-C), and 171.77 (C═O).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[C:11]([O:19][CH3:20])[CH:10]=2)=[CH:7][CH:8]=1)N.Cl.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:1][C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:17])[F:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1cc(-c2ccc(NN)nn2)ccc1OC(F)F
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CCO
Product: COc1cc(-c2ccc(N)nn2)ccc1OC(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
5.0 g (18 mmol) of 3-hydrazino-6-(4-difluoromethoxy-3-methoxyphenyl)pyridazine are dissolved in 50 ml of ethanol and 2.3 ml (27 mmol) of concentrated hydrochloric acid, 1 g of palladium/carbon and 3.4 g (54 mmol) of ammonium formate are added, and the mixture is heated to 80° C. After evolution of gases has ceased, the mixture is stirred for a further 3 hours, filtered to remove the catalyst, and the solution is stirred in 1 l water and made alkaline with concentrated ammonia, and the resulting precipitate is collected on a suction funnel. The filter cake is thoroughly washed with water and then dried and chromatographed in a 95:5 mixture of dichloromethane/methanol on silica gel. The appropriate fractions are concentrated in vacuo. 3 g (63.6%) of 3-amino-6-(4-difluoromethoxy-3-methoxyphenyl)pyridazine of m.p. 184° C. are obtained.
Reaction SMILES: C[O-].[Na+].C(OC)(=O)C.[CH3:9][O:10][C:11](=[O:29])[CH:12]=[C:13]1[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][CH:14]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1>CS(C)=O.C(OCC)(=O)C>[CH3:9][O:10][C:11](=[O:29])[CH2:12][C:13]1[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][C:14]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1
Reactant: COC(=O)C=C1CCC(C)(C)CC1c1cccc(OC)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COC(C)=O
Solvent: CS(C)=O
Product: COC(=O)CC1=C(c2cccc(OC)c2)CC(C)(C)CC1
Temperature: 100 °C
Yield: 100.2 %

Procedure:
Dissolve sodium methoxide (0.99 g, 18.4 mmol) in DMSO (37 ml) add methyl acetate (1 ml), add [2-(3-methoxy-phenyl)-4,4-dimethyl-cyclohexylidene]-acetic acid methyl ester (5.3 g, 18 mmol). Heat at 100° C. stirring over night. Dilute with ethyl acetate (50 ml), wash with brine 4× (30 ml), dry, and concentrate to give the title compound (5.2 g 98%): 1H NMR (CDCl3) δ 7.24-7.18 (m, 1H), 6.78-6.68 (m, 3H), 3.79 (s, 3H), 3.65 (s, 2H), 3.59 (s,1H), 2.95 (s,1H), 2.15-2.07 (m, 3H), 1.55(s, 3H), 1.49-1.46 (m,1H), 0.98 (s, 6H).
Reaction SMILES: BrC1C=CC(O)=C(C2(O)C3C(=CC=CC=3)N(CCCCC)C2=O)C=1.Br[C:26]1[C:27]([O:49][CH3:50])=[CH:28][C:29]([OH:48])=[C:30]([C:32]2(O)[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:33]2=[O:46])[CH:31]=1>>[OH:48][C:29]1[CH:28]=[C:27]([O:49][CH3:50])[CH:26]=[CH:31][C:30]=1[CH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:33]1=[O:46]
Reactant: CCCCCN1C(=O)C(O)(c2cc(Br)c(OC)cc2O)c2ccccc21
Agent: CCCCCN1C(=O)C(O)(c2cc(Br)ccc2O)c2ccccc21
Product: CCCCCN1C(=O)C(c2ccc(OC)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 15B, and making non-critical variations to replace 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(5-bromo-2-hydroxy-4-methoxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (83%): 1H NMR (300 MHz, CDCl3) δ 9.78-9.20 (br, 1H), 7.43-7.31 (m, 2H), 7.19 (t, 1H), 6.97 (d, 1H), 6.79 (d, 1H), 6.70-6.64 (m, 1H), 6.38 (dd, 1H), 5.02 (s, 1H), 3.77 (s, 3H), 3.70 (t, 2H), 1.75-1.63 (m, 2H), 1.40-1.25 (m, 4H), 0.87 (t, 3H); MS (ES+) m/z 326 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3](/[C:12](/I)=[CH:13]/[C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:22]([OH:26])[CH2:23][CH2:24][OH:25].[H-].[Na+]>>[F:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[C:14]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[CH:13][C:12]=2[O:25][CH2:24][CH2:23][CH2:22][OH:26]
Reactant: OCCCO
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Agent: [H-]
Agent: [Na+]
Product: O=C1Nc2ccc(F)c3c(OCCCO)cc(-c4ccc[nH]4)c1c23
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (198 mg, 0.5 mmol) in 1,3-propanediol (Fluka, 7.0 g, 92 mmol) was added NaH (Aldrich, 60%, 0.5 g, 12.5 mmol) in portions at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was heated to 110° C. for 2.5 hours. The reaction was quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were successively washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 50% ethyl acetate in hexanes) to afford 6-fluoro-5-(3-hydroxy-propoxy)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 51.5 mg, 31.6%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([F:11])([F:10])[F:9])=[N:4][NH:5][C:6]=1[CH3:7].CO.[C:14]([O:18]CC)(=[O:17])[C:15]#[CH:16]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([C:8]([F:9])([F:11])[F:10])=[N:4][N:5](/[CH:16]=[CH:15]/[C:14]([OH:18])=[O:17])[C:6]=1[CH3:7]
Reactant: C#CC(=O)OCC
Reactant: Cc1[nH]nc(C(F)(F)F)c1Cl
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(Cl)c(C(F)(F)F)nn1/C=C/C(=O)O
Temperature: 80 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To a vial containing 4-Chloro-5-methyl-3-trifluoromethyl-1H-pyrazole (2.83 g, 15.3 mmol) was added MeOH (5 mL) and ethyl propiolate (1.94 g, 19.7 mmol) and acetic acid (100 μL). The vial was capped and the reaction mixture was heated to 80° C. for 20 h. After cooling to room temperature, the volatiles were removed in vacuo to afford the crude products, which were purified by flash chromatography on silica gel (120 g) using gradient elution (0%-75% EtOAc in hexanes over 15 column volumes). The fractions containing the E and Z esters were collected separately and concentrated in vacuo. Each product was then transferred to a separate vial using THF (10 mL). Both vials were treated with a 1.0 N solution of LiOH (10 mL). The vials were heated to 40° C. After 2 h, the solutions were cooled, and each was diluted with water (50 mL). The pH was adjusted to 1 with 4 N HCl. Each aqueous phase was extracted with EtOAc (2×25 mL). The organic phases were dried over MgSO4 and concentrated in vacuo to afford (E)-3-(4-Chloro-5-methyl-3-trifluoromethylpyrazol-1-yl)-acrylic acid (2.21 g, 57% yield) HPLC retention time=2.18 minutes. MS (ES) [M−H]− expected 253.0, found 252.9; and (Z)-3-(4-Chloro-5-methyl-3-trifluoromethylpyrazol-1-yl)acrylic acid (749 mg, 19% yield). MS (ES) [M−H]− expected 253.0, found 252.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[C:28]([NH2:30])[N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>C(O)CCC.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:21]3[N:29]=[C:28]([NH2:30])[N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:6]=2[CH:19]=1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1nc(N)nc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Yield: 23 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine.2HCl (195 mg, 0.59 mmol), 6-chloro-9H-purin-2-ylamine (106 mg, 0.62 mmol) and DIPEA (415 μL, 2.38 mmol) in n-butanol (1 mL) was heated at 100° C. in a sealed vial for 24 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-60%, 0.1% NH4OH in acetonitrile/water) to afford 310 as a white solid (52 mg, 23%). LCMS (Method K): RT 2.89 min [M+H]+ 389.02. 1H NMR (CDCl3, 400 MHz): δ 7.67 (1H, dd, J=8.67, 4.59 Hz), 7.62-7.38 (5H, m), 7.20 (1H, s), 7.00 (1H, td, J=9.19, 2.45 Hz), 6.79 (1H, dd, J=8.61, 2.46 Hz), 5.65 (1H, s), 4.92 (1H, s), 1.64 (3H, d, J=6.94 Hz)