Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[N:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.[BH3:23].[OH:24][C:25]([C:28]([OH:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>[Pd].C(#N)C>[CH3:26][C:25]1([CH3:27])[C:28]([CH3:30])([CH3:29])[O:31][B:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:14]#[N:15])=[CH:4][CH:3]=2)[O:24]1
Reactant: B
Reactant: CC(C)(O)C(C)(C)O
Reactant: N#Cc1ccccc1-c1ccc(I)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(C)OB(c2ccc(-c3ccccc3C#N)cc2)OC1(C)C
Temperature: 25 °C
Yield: 57.9 %

Procedure:
Add 2-(4-iodophenyl)benzenecarbonitrile (10.0 grams, 0.0328 moles, preparation 57), acetonitrile (100 mL), and triethylamine (8.50 grams, 0.084 moles) to a 250 mL 3-neck flask equipped with a condenser, internal temperature probe, septum, and heating mantle and stir under a nitrogen atmosphere. Add pinacol borane (6.7 grams, 0.0524 moles) and palladium black (0.174 grams, 0.00164 moles). Heat the reaction mixture to reflux and stir at reflux for 135 minutes. Cool the reaction mixture to ambient temperature and filter to remove palladium black Concentrate the filtrate to a solid under reduced pressure (15-25 mm) and dissolve the solid in isopropyl acetate (100 mL) and water (50 mL). Transfer the resulting mixture to a separatory funnel and separate phases. Discard the aqueous phase and dilute the organic phase with heptane (50 mL), water (50 mL) and dichloromethane (30 mL). Separate the phases and discard the aqueous phase. Add water (50 mL) and warm the mixture to 60° C. Stir at 60° C. for 5 minutes, then separate the phases. Extract the aqueous phase with methyl-tert-butyl ether (30 mL), separate the phases and discard the aqueous phase. Combine the organic phases and concentrate to an oil (12.5 grams) under reduced pressure. Dissolve the oil in a mixture of methyl-tert-butyl ether (1.5 mL) and dichloromethane (28.5 mL) and apply the solution to a 40 gram silica gel column. Elute the sample from the column using a mixture of methyl-tert-butyl ether (7.5 mL) and dichloromethane (142.5 mL). Concentrate the resulting solution to an oil (10.2 grams) under reduced pressure (15-25 mm). Observe that the oil spontaneously crystallizes upon standing at room temperature. Suspend the resulting solid in pentane (30 mL) and filter to recover the solid. Suspend the solids in a mixture of methyl-tert-butyl ether (3 mL) and pentane (70 mL), then filter the suspension to recover the solid product. Vacuum dry the solid at 25° C. under reduced pressure (15-25 mm). Suspend the solid again in a mixture of methyl-tert-butyl ether (3 mL) and pentane (50 mL), filter and dry the solid at 25° C. under reduced pressure (15-25 mm) to provide the title compound (5.8 g, 0.019 moles) in 57.9% yield. 1H NMR (CDCl3, 500.0 MHz): δ 7.92 (app. d, 2H, J=8); 7.75 (dd, 1H, J=1, 7.5); 7.62 (td, 1H, J=1.5, 7.5); 7.55 (app. d, 211, J=8); 7.50 (dd, 1H, J=1, 7.5); 7.43 (td, 1H, 1, 7.5); 1.35 (s, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:38][CH2:39][CH2:40][Cl:41]>O>[Cl:41][CH2:40][CH2:39][CH2:38][O:25][C:22]1[CH:23]=[CH:24][C:19]2[N:18]=[CH:17][N:16]([C:10]3[S:11][C:12]([C:13]([NH2:15])=[O:14])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]=3)[C:20]=2[CH:21]=1
Reactant: ClCCCBr
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OCCCCl)cc32)nc1-c1cccc(Cl)c1
Yield: 79.4 %

Procedure:
A mixture of 0.370 g (1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 3 mL of dimethylformamide, 1.6 g (5 mmole) of cesium carbonate and 0.297 mL (3 mmole) of 1-bromo-3-chloro-propane was heated at 100 degrees for 1 hour. The cooled mixture was diluted with 20 mL of water and the resulting precipitate collected by filtration. The solid was triturated with diethyl ether to give 0.355 g of 2-[6-(3-chloro-propoxy)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.34a) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13](=[NH:16])SC)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[CH2:17]([O:24][C:25](=[O:34])[NH:26][CH2:27][CH2:28][CH2:29][C@H:30]([NH2:33])[CH2:31]N)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(O)C>[CH2:17]([O:24][C:25](=[O:34])[NH:26][CH2:27][CH2:28][CH2:29][C@H:30]1[CH2:31][NH:16]/[C:13](=[N:12]\[C:10]([C:3]2[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=2)=[O:11])/[NH:33]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NC[C@@H](N)CCCNC(=O)OCc1ccccc1
Solvent: CC(C)O
Product: Nc1nc(N)c(C(=O)/N=C2\NC[C@H](CCCNC(=O)OCc3ccccc3)N2)nc1Cl
Temperature: 85 °C
Reaction time: 66 h

Procedure:
1-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) (0.97 g, 3.72 mmol) is stirred in a three necked round bottom flask fitted with a bleach trap and condenser and ((S)-4,5-Diamino-pentyl)-carbamic acid benzyl ester (Intermediate S) (0.85 g, 3.38 mmol) in propan-2-ol (20 ml) is added. The reaction mixture is stirred at 85° C. for 66 hours. Purification by catch and release resin (SCX-2) followed by elution through a silica pad flushed with EtOAc, ethanol and MeOH yields the title compound as an orange foam; [M+H]+ 447.1
Reaction SMILES: [C:1]1(CO)CCCCC=1.[O:9]1[C:13]2([CH2:18][CH2:17][C:16]([CH2:19][OH:20])=[CH:15][CH2:14]2)[O:12][CH2:11][CH2:10]1>>[O:9]1[CH2:10][CH2:11][O:12][C:13]21[CH2:18][CH2:17][C:16]1([CH2:19][OH:20])[CH:15]([CH2:1]1)[CH2:14]2
Reactant: OCC1=CCC2(CC1)OCCO2
Reactant: OCC1=CCCCC1
Product: OCC12CCC3(CC1C2)OCCO3

Procedure:
Following the procedure as described in Example 342 Step 2 and making non-critical variations to replace cyclohexenylmethanol with 1,4-dioxaspiro[4.5]dec-7-en-8-ylmethanol, the title compound was obtained as a colourless liquid (4.0 g, 96%): 1H NMR (300 MHz, CDCl3) δ 3.92-3.84 (m, 4H), 3.48 (d, J=10.8 Hz, 1H), 3.26 (d, J=10.9 Hz, 1H), 2.21-2.0 (m, 2H), 1.94-1.86 (m 1H), 1.77-1.65 (m, 1H), 1.60-1.51 (m, 1H), 1.40-1.30 (m, 1H), 0.58 (dd, J=9.2, 4.8 Hz, 1H), 0.40 (t, J=5.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Br:9])[C:3]=1[Br:10].[Cl:11][CH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].C1([O-])C=CC=CC=1>[OH-].[Na+].COCCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[CH2:12][Cl:11])=[C:4]([Br:9])[C:3]=1[Br:10]
Reactant: O=C(Cl)c1ccccc1CCl
Reactant: Oc1ccc(Br)c(Br)c1Br
Agent: [Na+]
Agent: [O-]c1ccccc1
Agent: [OH-]
Solvent: COCCO
Product: O=C(Oc1ccc(Br)c(Br)c1Br)c1ccccc1CCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
In a two-liter three-necked flask, 40 g of sodium hydroxide was dissolved in 950 ml of methyl glycol at 60° C, and then 331 g (= 1 mole) of tribromophenol was stirred in, and then 189 g (= 1 mole) of o-chloromethyl benzoyl chloride was added, drop by drop, with stirring, over a period of 13/4 hours, at a reaction mixture temperature not exceeding 40° C, into the clear phenolate solution, cooled to 30° to 40° C. Stirring was then continued for one hour at room temperature; the mixture was then cooled to 0° C, the crystallizate was suction filtered and washed free of sodium chloride with water, and dried at 80° C in a vacuum drying chamber. 397 g (= 82% yield) was obtained of o-chloromethylbenzoic acid tribromophenyl ester melting at 180°-110° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20](Br)=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1>>[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH2:1])=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Nc1ccccc1B(O)O
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: Nc1ccccc1-c1ccc(Cn2ccnc2)cn1

Procedure:
Synthesized using 2-aminophenylboronic acid (173 g, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 120 mg, 0.48 mmol, 76%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.17 (s, 2H), 6.74-6.79 (m, 2H), 6.93 (t, J=1.3 Hz, 1H), 7.13 (bs, 1H), 7.16-7.19 (m, 1H), 7.49-7.53 (m, 2H), 7.62 (s, 1H), 7.66 (d, J=8.2 Hz, 1H). 8.48 (d, J=1.8 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.2, 117.3, 117.6, 119.1, 121.1, 122.2, 128.7, 129.3, 130.2, 130.3, 135.8, 137.3, 146.6, 146.7, 159.7; MS (ESI): m/z=250.71 [M+H]+.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:13][C:14]1([C:17]([OH:19])=O)[CH2:16][CH2:15]1.[Cl:20][C:21]1[C:33]([CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:32][CH:31]=[CH:30][C:22]=1[O:23][C@H:24]1[CH2:27][C@H:26]([CH2:28][NH2:29])[CH2:25]1>C1COCC1>[ClH:20].[Cl:20][C:21]1[C:33]([CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:32][CH:31]=[CH:30][C:22]=1[O:23][C@H:24]1[CH2:27][C@H:26]([CH2:28][NH:29][C:17]([C:14]2([CH3:13])[CH2:16][CH2:15]2)=[O:19])[CH2:25]1
Reactant: CC1(C(=O)O)CC1
Reactant: NC[C@H]1C[C@H](Oc2cccc(CN3CCCC3)c2Cl)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC1(C(=O)NC[C@H]2C[C@H](Oc3cccc(CN4CCCC4)c3Cl)C2)CC1
Product: Cl

Procedure:
CDI (110 mg, 0.70 mmol) was added to a solution of 1-methylcyclopropanecarboxylic acid CAS 6914-76-7 (102 mg, 1.0 mmol) in THF (2 ml) at RT under stirring, the mixture was stirred at RT for 1 h. Example 386, ({trans-3-[2-Chloro-3-(pyrrolidin-1-ylmethyl)phenoxy]cyclobutyl}methyl) amine (200 mg, 0.7 mmol) was added to the mixture and the solution was stirred at RT for 20 h and evaporated. The residue was purified by chromatography (silica gel, 63-100 μm, 5 g, hexane/CHCl3 20:80→0:100, then CHCl3/MeOH 100:0→95:5). The residue was dissolved in ether (1 mL). 4N HCl/dioxane (0.20 mL) was added, and the reaction mixture was evaporated to dryness. The obtained crystals were washed with ether and dried in vacuo to give the title compound (135 mg, 48%) as beige crystals. LC/MS data: 377.1 (M+H) (calculated for C21H29ClN2O2 376.93). 1H NMR-data (DMSO-d6): 10.53 (br.s, 1H, NH+); 7.49-7.78 (m, 1H, NH); 7.32-7.43 (m, 2H, Ar—H); 6.95-7.03 (m, 1H, Ar—H); 4.80-4.92 (m, 1H), 4.42-4.56 (m, 2H); 3.39-3.47 (m, 2H); 3.18-3.25 (m, 2H); 3.07-3.18 (m, 2H); 2.39-2.47 (m, 1H); 2.27-2.34 (m, 2H); 1.97-2.17 (m, 4H); 1.84-1.95 (m, 2H); 1.25 (s, 3H); 0.92-0.96 (m, 2H), 0.46-0.52 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[C:6](=[O:33])[C:5]([C:34](O)=[O:35])=[N:4]1)[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.C(O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[C:6](=[O:33])[C:5]([CH2:34][OH:35])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C(=O)O)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCO
Product: CCn1nc(CO)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a suspension of 1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carboxylic acid (2.25 g, 4.59 mmol) in tetrahydrofuran (THF) (60 mL) was added triethylamine (2.110 mL, 15.14 mmol) and ethyl chloroformate (1.322 mL. 13.76 mmol). The resulting yellow solution was stirred at room temperature for 2 h, and was then added to a solution of sodium borohydride (2.083 g, 55.0 mmol) in ethanol (60 mL). After being stirred for 2 h, the reaction was quenched by addition of water (5 mL). The organic solvent was removed in vacuo, the residue was then taken in water (50 mL) and extracted with dichloromethane (2×50 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by automatic silica gel column chromatography (Combiflash RF), eluting with methanol/dichloromethane (0-10%) to afford 1-ethyl-3-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy)cinnolin-4(1H)-one (1.97 g, 3.64 mmol, 79% yield) as a white solid. LCMS: (M+H)+: 477.1
Reaction SMILES: [C:1]([C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH2:4][OH:5])#[N:2].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:20][S:21]([O:5][CH2:4][C:3]([C:1]#[N:2])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC(CO)(c1ccc(Cl)cc1)c1ccccc1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(C#N)(c1ccc(Cl)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-cyano-2-(2-chlorophenyl)-2-(4-chlorophenyl)ethanol (18 g., 0.06 mole) and methane sulfonyl chloride (7.8 g., 0.07 mole) in 200 ml. of benzene is added dropwise at 10° C., 7.5 g. (0.08 mole) of triethylamine. The reaction mixture is stirred at room temperature for 30 minutes and then heated on a steam bath for another 30 minutes. The precipitate formed is filtered and the filtrate is washed with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 22 g. of product; mp 124°-7° C., which is identified by nmr.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.[C:19]1([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][C:30]=2B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:14]([C@H:6]1[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]2[N:3]=[C:2]([C:30]3[CH:29]=[CH:28][N:27]=[CH:26][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7]1=[O:13])[CH3:15]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Reactant: CC1(C)OB(c2ccncc2-c2ccccc2)OC1(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3-c3ccccc3)nc2N1C(C)C

Procedure:
The title compound was prepared similarly to the methods described in Example 5, with Intermediate C instead of Intermediate B and with 3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Boronic Acid 2) instead of pyridin-4-ylboronic acid. LCMS: 388.2 m/z (M+H)+; ret. Time: 6.56 min (Analytical Method C).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH3:17])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.CS(C)=O.[C-:22]#[N:23].[Na+]>O>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([CH3:17])=[CH:4][C:3]=2[CH2:2][C:22]#[N:23])=[CH:11][CH:12]=1
Reactant: Cc1ccc(Oc2ccc(C)cc2CCl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(Oc2ccc(C)cc2CC#N)cc1
Temperature: 36 °C
Reaction time: 4 h

Procedure:
A solution of 108 g. of 3-chloromethyl-4-(4-methyl-phenoxy)-toluene in 70 ml. of dimethylsulfoxide is added dropwise at 20°-25° C. to a suspension of 23 g. of sodium cyanide in 35 ml. of dimethylsulfoxide. The mixture is subsequently stirred for 4 hours at 36° C., then diluted with 1 liter of water and extracted three times with benzene. The benzene extracts are washed three times with water, then dried over sodium sulfate and evaporated in vacuo, and there is obtained crude 2-(4-methyl-phenoxy)-5-methyl-phenylacetonitrile as a brown oil.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9](N(OC)C)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([Mg]Br)([CH3:25])=[CH2:24]>C1COCC1.CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O>[CH:1]1([CH2:7][C@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[C:9](=[O:10])[C:23]([CH3:25])=[CH2:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CON(C)C(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: C=C(C)[Mg]Br
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
To (S)-tert-butyl (3-cyclohexyl-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (12.2 g, 38.9 mmol) in THF (150 mL) at 0° C. was added isopropenylmagnesium bromide (71.2 mL of a 1.5 N solution in methyl-THF, 0.107 mol) dropwise. After stirring at 0° C. for 2 h the mixture was quenched with heptane/citric acid (1:1). The product was extracted with EtOAc (2×), washed with brine, dried with sodium sulfate, filtered, and concentrated. The crude product was triturated from cold (0° C.) methanol to provide (S)-tert-butyl (1-cyclohexyl-4-methyl-3-oxopent-4-en-2-yl)carbamate (5.36 g, 49%) as a colorless crystalline solid. MS (EI) for C17H29NO3, found 196.2 [M-Boc]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:16])[CH2:7][CH2:8][C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(=O)(O)[O-]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:16])[CH2:7][CH2:8][C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCc2ccc(=O)n3c2N1C[C@H]3CO
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1CN2C(=O)CCc3ccc(=O)n1c32
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (1S)-1-(hydroxymethyl)-1,2,5,6-tetrahydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (1.909 g, 8.67 mmol) in DCM (100 ml) at 0° C. under argon was treated with triethylamine (1.450 ml, 10.40 mmol) and then methanesulfonyl chloride (0.743 ml, 9.54 mmol) and then allowed to warm to rt and stirred at rt for 1 h. The reaction mixture was then treated with saturated aqueous bicarbonate (100 ml) and the mixture was extracted with DCM (2×100 ml). The combined organic solvents were then dried (MgSO4), filtered and evaporated to give the crude intermediate [(2S)-4,9-dioxo-1,2,8,9-tetrahydro-4H,7H-imidazo[1,2,3-ij]-1,8-naphthyridin-2-yl]methyl methanesulfonate. This was dissolved in dry acetonitrile (100 ml) and then treated with pyridine (1.402 ml, 17.34 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (3.47 g, 17.34 mmol) and heated at 70° C. for 20 h. After 20 h more 1,1-dimethylethyl 4-piperidinylcarbamate (3.47 g, 17.34 mmol) and pyridine (1.402 ml, 17.34 mmol) were added and the temperature was increased to reflux (heating block 95° C.) and reaction was stirred at this temperature for a further 4 h. The reaction mixture was then evaporated, saturated aqueous NaHCO3 (200 ml) was then added and the mixture was extracted with DCM (3×200 ml). The combined organic solvents were then dried (MgSO4), filtered and evaporated to give the crude product as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(OP([CH2:33][C:34]#[N:35])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[CH:33][C:34]#[N:35])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(OC)cc(C(=O)c2cc(OC)c(OC)c(OC)c2)c1
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2cc(OC)c(OC)c(OC)c2)c1
Yield: 74.5 %

Procedure:
(3,5-Dimethoxy-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone (0.55 g, 1.7 mmol), cyanomethylphosphonic acid diethyl ester (0.52 ml, 3.3 mmol) in anhydrous THF (20 ml), and potassium bis-(trimethylsilyl)amide (0.66 g, 3.3 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile. The crude material was purified by flash column chromatography to give a solid (450 mg, 81%): mp, 135-137° C.; 1H NMR (DMSO-d6) δ 6.67-6.63 (m, 3H), 6.51 (d, J=1 Hz, 2H), 6.36-6.33 (m, 1H), 3.77-3.71 (m, 15H); 13C NMR (DMSO-d6) δ 161.33, 161.16, 160.38, 160.29, 152.70, 152.65, 139.73, 139.63, 138.73, 138.59, 132.82, 132.09, 118.14, 118.05, 107.24, 106.82, 106.62, 106.01, 102.36, 96.32, 95.77, 60.11, 56.06, 55.39; Anal. Calcd. For C20H21NO5: C, 67.59; H, 5.96; N, 3.94. Found: C, 67.44; H, 5.73; N, 3.77.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([O:24]C)=[CH:11][CH:10]=3)[CH3:2].B(Br)(Br)Br.ClCCCl.[OH-].[Na+]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([OH:24])=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(NCC3CCCCC3)c3cc(OC)ccc3nc21
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCCl
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(O)ccc3nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-ethyl-6-methoxy-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine (5.4 g, 0.016 mol), boron tribromide (48 ml, 0.048 mol) and 1,2-dichloroethane (250 ml) was stirred at room temperature overnight. The reaction mixture was stirred with 1 volume of water, made basic with NaOH and the layers were separated. The basic layer was acidified with acetic acid and the yellow precipitate which formed was collected by filtration, washed with water and dried. The product was recrystallized from hot acetonitrile/methanol to afford 1-ethyl-6-hydroxy-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as a yellow powder, m.p. 223°-224° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:11]2[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:11]3[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1sc2nc(Cl)nc(NCCc3ccc4c(c3)OCO4)c2c1C
Reactant: Cc1ncc[nH]1
Product: Cc1sc2nc(-n3ccnc3C)nc(NCCc3ccc4c(c3)OCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6-dimethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6-dimethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:19]=[CH:18][CH:17]=[C:15]([NH2:16])[CH:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Nc1cccc(Br)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: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2cc(F)cc(F)c2)c1
Temperature: 25 °C

Procedure:
3,5-difluorophenyl-boronic acid (0.138 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in DME (3 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.610 mL, 1.22 mmol) and Pd(PPh3)4 (0.02 g, 0.017 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the solvent was removed under vacuum from fractions containing product.