Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[C:8]1([C:14]#[C:15][C:16]2[CH:34]=[CH:33][C:19]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29](=[O:32])(=[O:31])[NH2:30])=[O:21])=[CH:18][CH:17]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:1][C:2]([CH3:7])=[CH:3][C:4]([NH:30][S:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:33]=[CH:34][C:16]([C:15]#[C:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:17][CH:18]=1)(=[O:31])=[O:32])=[O:5]
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Reactant: CC(C)=CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)=CC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
In a stream of nitrogen and at 0° C., 0.10 ml (0.96 mmol) of 3,3-dimethylacryloyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 300 mg (0.80 mmol) of 4-phenylethynyl-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 10 and 195 mg (1.60 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 183 mg (yield: 50.0%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])[C@H:3]1[C:13](OC(C)(C)C)=[O:14].[C:21]([C@@H:23]([OH:37])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:25]=1)#[N:22]>>[CH3:1][C:2]1([CH3:20])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])[C@H:3]1[C:13]([O:37][C@H:23]([C:21]#[N:22])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:25]=1)=[O:14]
Reactant: C#CCOC(=O)/C=C\[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Product: C#CCOC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Yield: 116.6 %

Procedure:
Using the procedure of Step C of Example 13, 1.59 g of the product of Step A and 1.8 g of (S)α-cyano-3-phenoxy-benzyl alcohol were reacted and after 2 hours, the mixture was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 9-1 cyclohexane-ethyl acetate mixture yielded 2.86 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[Z-2-(propargyloxycarbonyl)-ethenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+44°±1.5° (c=1% in CHCl3).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@:13]32[C@H:8]([C@H:9]([C:21](=O)[CH2:22]Br)[CH2:10][CH2:11][C@@H:12]3[CH3:20])[CH:7]=[C:6]1[CH3:25])(=[O:3])[CH3:2].[C:26]([NH2:30])(=[S:29])[CH2:27][CH3:28]>C(O)C>[C:1]([O:4][C@H:5]1[C@@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@@:13]32[C@H:8]([C@H:9]([C:21]2[N:30]=[C:26]([CH2:27][CH3:28])[S:29][CH:22]=2)[CH2:10][CH2:11][C@H:12]3[CH3:20])[CH:7]=[C:6]1[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C(C)=C[C@H]2[C@H](C(=O)CBr)CC[C@H](C)[C@]23OC(C)(C)O[C@@H]13
Reactant: CCC(N)=S
Solvent: CCO
Product: CCc1nc([C@@H]2CC[C@@H](C)[C@]34OC(C)(C)O[C@H]3[C@H](OC(C)=O)C(C)=C[C@@H]24)cs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.7 %

Procedure:
To a stirred solution of (3aS,4R,6aS,7R,10S,10aS)-7-(2-bromoacetyl)-2,2,5,10-tetramethyl-4,6a,7,8,9,10-hexahydro-3aH-naphtho[1,8a-d][1,3]dioxol-4-yl acetate (Preparation 164, 500 mg) in ethanol (5 ml) was added thiopropionamide (110 mg). The reaction mixture was stirred at room temperature for 24 hours and then partitioned between saturated aqueous sodium chloride and ethyl acetate. The organic phase was dried (MgSO4), evaporated and purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane (1:4) to give the product as a gum (345 mg).
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[O:19][CH3:20].[CH2:21]([Li])CCC.CN(CCN(C)C)C.IC>C1COCC1.O>[CH3:20][O:19][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[C:2]=1[CH3:21]
Reactant: COc1ccc(-c2cc3c(Br)c(OC)ccc3o2)cc1
Reactant: [Li]CCCC
Agent: CN(C)CCN(C)C
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cc3c(C)c(OC)ccc3o2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
4-Bromo-5-methoxy-2-(4-methoxyphenyl)-benzofuran 133 (0.282 g, 0.85 mmol) was taken into 20 mL of THF and cooled to 0° C. Then butyllithium (0.68 mL of a 2.5M solution in THF, 1.7 mmol) was added dropwise and allowed to stir for 20 minutes. Then TMEDA (0.256 mL, 1.7 mmol) was added followed by iodomethane (1.06 mL, 17 mmol). The reaction was allowed to stir overnight at room temperature. The reaction was poured into water and extracted with ethyl acetate. The combined organics was washed with water (2×), brine (1×), dried over magnesium sulfate filtered and concentrated. The resulting material was purified by column chromatography on silica gel, using a gradient of 1% to 3% ethyl acetate in hexane. The first fractions contained the product and another side product. This fraction was added to another synthesis of this compound (starting with 0.250 g 4-Bromo-5-methoxy-2-(4-methoxyphenyl)-benzofuran) for the final cleavage reaction.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].C([N:12](CC)CC)C.CCN(C(C)C)C(C)C.C(Cl)Cl>C1COCC1.C(Cl)(Cl)Cl>[C:2](=[O:3])([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])[NH2:12]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(=O)OCC(Cl)(Cl)Cl

Procedure:
Scheme 1 depicts a first synthesis of the boronic acid pinacol ester intermediate compound [1]. Specifically, a 4-nitrobenzoic acid [A] is converted to the corresponding amide [B] using an amine such as R7R8NH, a coupling agent such as EDCI.HCl, DCC, HBTU, or HATU, an additive such as HOBt or HOAt, a base such as TEA or DIPEA and solvent such as DMF, THF, or DCM. In one embodiment, the amine may be NH3, NH2CH3, NH(CH3)2, morpholine, piperidine, 1-methyl-piperazine and N(CH3)2CH2CH2N(CH3)2, among others. Typically, this is performed at rt such as about 25 to about 30° C. for about 10 to about 15 h such as about 10 h. The 4-nitro amide [B] is then reduced to the corresponding amine [C] using H2 and a catalyst such as Pd/C 10%, PtO2, or Pd(OH)2. Typically, the reduction is performed under pressures such as 60 psi, in a solvent such as MeOH, dioxane, or ethylacetate, for about 3 to about 5 h such as about 3 h. Amine [C] is then converted to urea [D] using an appropriately substituted isocyanate such as 4-bromophenyl isocyanate. This reaction is typically performed in the presence of a base such as TEA or DIPEA and solvent such as CH2Cl2, CHCl3, or THF at about rt such as about 25 to about 30° C. for about 5 to about 15 h such as about 12 h. As one alternative method, amine [α] can be converted to the corresponding 2,2,2-trichloro-ethyl carbamate and then reacted with an appropriately substituted aniline or pyridinyl amine, to produce the desired urea [D]. For example, amine [C] would typically be treated with 2,2,2-trichloroethyl chloroformate in the presence of a base such as triethylamine or DIPEA, in a solvent such as CH2Cl2, CHCl3, or THF, at temperatures such as 0° C. to about 30° C. for about 30 minutes to 5 hours, to produce the 2,2,2-tri-chloroethyl carbamate intermediate. Then the 2,2,2-trichloroethyl carbamate intermediate is typically reacted with the aniline or pyridinyl amine in the presence of a base such as triethylamine or DIPEA, in a solvent such as toluene, 1,4-dioxane or THF, at about room temperature up to elevated temperatures such as about 110° C. for about 1 to 16 hours. This alternative two-step procedure provides the urea [D]. Intermediate boronic acid pinacal ester [1] is then formed by reacting urea [D] with bis(pinacolato)diboron. This reaction may be performed in the presence of a weak base such as KOAc, palladium catalyst such as Pd(dppf)Cl2.DCM or Pd(dppf)Cl2, in a solvent such as 1,4-dioxane or DMF. Desirably, the reaction is performed at elevated temperatures such as the reflux temperatures of the solvent. In one embodiment, this reaction is performed at about 80 to about 120° C. for about 2 to about 15 h. In another embodiment, this reaction is performed at about 110° C. for about 10 h.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[C:10]([CH3:29])([CH3:28])[CH2:9]1)=O)(C)(C)C.[F:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38][NH2:39])[CH:34]=[CH:35][CH:36]=1>>[CH3:29][C:10]1([CH3:28])[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:39][CH2:38][CH2:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=3)[N:22]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: NCCc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)C(C)(C)C1
Product: CC1(C)CNCCN1Cc1cccc(-c2ccnc(NCCc3cccc(F)c3)n2)c1

Procedure:
Intermediate 141 was coupled with 2-(3-fluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H3O+of 438. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.75 (s, 1H) 8.36 (d, 2H) 7.96 (d, 1H) 7.65 (m, 2H) 7.27 (m, 1H) 7.18 (m, 2H)) 6.92 (m, 1H) 4.54 (s, 2H) 3.96 (t, 2H) 3.72 (s, 2H) 3.59 (t, 2H) 3.35 (t, 2H) 3.08 (t, 2H) 1.74 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([F:42])=[C:26]([CH:41]=1)[O:27][C:28]1[N:33]=[C:32]2[S:34][C:35]([NH:37][C:38](=[O:40])[CH3:39])=[N:36][C:31]2=[CH:30][CH:29]=1.O>C(Cl)(=O)C(Cl)=O.CN(C)C(=O)C>[C:38]([NH:37][C:35]1[S:34][C:32]2[C:31]([N:36]=1)=[CH:30][CH:29]=[C:28]([O:27][C:26]1[CH:41]=[C:22]([NH:21][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[C:2]=3[Cl:1])[CH:23]=[CH:24][C:25]=1[F:42])[N:33]=2)(=[O:40])[CH3:39]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Reactant: CC(=O)Nc1nc2ccc(Oc3cc(N)ccc3F)nc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)ccc3F)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (0.11 g, 0.5 mmol) produced in Example C61(v) in oxalyl chloride (0.5 mi) was added N,N-dimethylformamide (40 μL), and the mixture was stirred at room temperature for 30 min, and concentrated to dryness under reduced pressure. This was dissolved in a mixture of N,N-dimethylacetamide (1 mL) and tetrahydrofuran (1 mL), and the solution was added dropwise to a solution of N-[5-(5-amino-2-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]acetamide (0.11 g, 0.33 mmol) in N,N-dimethylacetamide (1 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr, and poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (52 mg, 30%) as colorless crystals.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1([CH2:26][CH2:27][CH2:28][CH:29]([CH2:39]O)[CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Br)(Br)(Br)[Br:42]>C(Cl)Cl>[Br:42][CH2:39][CH:29]([CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:28][CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCC(CCCc1ccccc1)CCCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCC(CCCc1ccccc1)CCCc1ccccc1
Reaction time: 16 h
Yield: 88.7 %

Procedure:
A solution of triphenylphosphine (0.885 g, 3.37 mmol) in methylene chloride (5 mL) was added to a solution of yield 1,7-diphenyl-4-hydroxymethylheptane (0.666 g, 2.36 mmol) and carbon tetrabromide (1.10 g, 3.33 mmol) in methylene chloride (10 mL) at 0° C. under nitrogen. After 16 h, the solvent was removed under reduced pressure and the residue was purified by silica gel chromatography, eluting with methylene chloride/hexanes (5% to 10%) to provide 4-bromomethyl-1,7-diphenylheptane (0.723 g, o9%). 1H NMR (300 MHz, CDCl3): δ 1.45 (m, 4 H), 1.63 (m, 5 H), 2.62 (t, 4 H, J=7.6), 3.46 (d, 2 H, J=4.7), 7.25 (m, 10 H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[O:7][C:8]1[N:23]=[CH:22][CH:21]=[CH:20][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)=[O:11])(=[O:3])[CH3:2].C[Li].[CH2:29]1COCC1.C1(C(C)C)C=CC=CC=1>O1CCCC1>[OH:3][C:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[O:7][C:8]1[N:23]=[CH:22][CH:21]=[CH:20][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)=[O:11])([CH3:29])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccncc2)c1
Agent: [Li]C
Solvent: CC(C)c1ccccc1
Product: CC(C)(O)c1cccc(Oc2ncccc2C(=O)NCc2ccncc2)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3-Acetyl-phenoxy)-N-pyridin-4-ylmethyl-nicotinamide (0.180 grams, 0.51 mmole) in tetrahydrofuran (20 ml) at −78° C. 1.0 M methyl lithium in THF/cumene (1.14 ml, 1.14 mmole) was added and stirred at −78° C. for 1 hour. The reaction was quenched with water and diluted with ethyl acetate. The organics were washed with water and brine, dried over MgSO4, filtered and concentrated to give a product which was purified by chromatography on silica eluting with ethyl acetate to give a white foam. MS (m/e) 364 (M++1); 1H NMR (CDCl3) d 1.58 (6H, s), 4.70 (2H, d, J=5.81 Hz), 7.0-8.7 (12H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:7]2[C:6]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:5][CH:4]=1.[CH2:20]([OH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[CH2:20]([O:27][CH2:18][CH2:17][C:16]([C:6]1[C:7]2[N:8]([N:9]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:11]=2)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCc1ccccc1
Reactant: CCC(=O)c1ccc(OC)n2nc(C(F)(F)F)cc12
Solvent: ClCCl
Product: COc1ccc(C(=O)CCOCc2ccccc2)c2cc(C(F)(F)F)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
A solution of the compound of Example 319 (3.42 g) and benzyl alcohol (1.37 g) in dichloromethane (50 mL) was added to dichloro bis(acetonitrile) palladium (II) (329 mg) in a stream of argon gas. The mixture was stirred at room temperature overnight, followed by addition of benzyl alcohol (500 mL) and stirring overnight. The insoluble material was removed by filtration through Celite. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2). The product was further purified by amino-silica gel column chromatography (hexane:ethyl acetate=3:2) to afford the title compound as a pale yellow powder (2.47 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[CH:7]=O.C([N:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25])(=O)C.[H-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[CH:7]=[C:22]1[CH2:23][CH2:24][NH:20][C:21]1=[O:25]
Reactant: CN1CCN(c2ccc(F)cc2C=O)CC1
Reactant: CC(=O)N1CCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(F)cc2C=C2CCNC2=O)CC1
Reaction time: 2.5 h
Yield: 33.5 %

Procedure:
A solution of 9.0 g (40.5 mmol) of 5-Fluoro-2-(4-methyl-piperazin-1-yl)-benzaldehyde and 5.1 g (40.5 mmol) of N-acetylpyrrolidinone in 80 mL of tetrahydrofuran is slowly added to a 0° C. solution of 5.4 g (133.6 mmol) of sodium hydride in 80 mL of tetrahydrofuran over a 2 hour period. After 2.5 hour at 0° C., the reaction is quenched with sat. ammonium chloride and extracted with methylene chloride. The organic layer is dried with magnesium sulfate and concentrated to provide a yellow solid. Recrystallization from ethyl acetate and diispropyl ether provided 3.92 g (33%) of 3-[5-Fluoro-2-(4-methyl-piperazin-1-yl)-benzylidene]-pyrrolidin-2-one as a white solid. Diagnostic C13 NMR (100 MHz, CDCl3) 26.4, 39.9, 46.1, 52.9, 55.3, 115.2, 115.5, 115.8, 116.0, 120.2, 120.3, 126.7, 131.1, 148.9, 157.3, 159.7, 172.8; MS m/z 290.3 (M+1).
Reaction SMILES: BrC1C(C)=CC(C)=CC=1C.C([Li])CCC.CCCCCC.[CH2:22]([C:24]1([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([O:36][CH3:37])[CH:31]=2)[O:29][CH2:28][CH2:27][CH2:26][O:25]1)[CH3:23].CN([CH:41]=[O:42])C>C1COCC1>[CH2:22]([C:24]1([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([O:36][CH3:37])[C:31]=2[CH:41]=[O:42])[O:29][CH2:28][CH2:27][CH2:26][O:25]1)[CH3:23]
Reactant: CCC1(c2ccnc(OC)c2)OCCCO1
Reactant: CN(C)C=O
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC1(c2ccnc(OC)c2C=O)OCCCO1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
A stirred solution of 6.87 mL 2-bromomesitylene (44.78 mmol, 2.0 eq) in 44 mL THF was cooled to −45° C. 35.8 mL n-butyllithium in hexane (2.5 M, 89.56 mmol, 4.0 eq) were added within 20 min. The resulting white suspension was then allowed to warm to 0° C. within 2.5 h. At −10° C. the reaction mixture became a clear solution. Stirring was continued for an additional hour at 0° C. The solution was cooled to −10° C. and a solution of 5.00 g 4-(2-ethyl-[1,3]dioxan-2-yl)-2-methoxy-pyridine (22.39 mmol), as obtainable from Example 3, in 15 mL THF was added over 15 min under vigorous stirring. The resulting brown suspension was allowed to warm to 10° C. within 2.5 h. The cooling bath was then removed and stirring was continued at room temperature for an additional hour. The clear brown solution was then cooled to −23° C. and 5.19 mL DMF (67.17 mmol, 3.0 eq) were added. The mixture was allowed to slowly warm up to room temperature overnight. The reaction was quenched by addition of 100 mL saturated aqueous NH4Cl. After 15 min, 50 mL water were added. The mixture was extracted three times with 150 mL, in total with 450 mL TBME. The combined organic phases were washed two times with 300 mL, in total 600 mL brine, dried over 20 g Na2SO4 (30 min) and filtered. The filter cake was washed with 40 mL TBME. After evaporation of solvent in a rotary evaporator (40° C./10 mbar), the crude product (12.048 g, 214% by weight) was obtained as a brown oil which was then purified by silica gel filtration (97 g silica gel) using a gradient elution with 2.0 L heptane/ethyl acetate (30:1) and 1.4 L heptane/ethyl acetate (5:1). Evaporation to dryness of the second fraction in a rotary evaporator (40° C./10 mbar) yielded the title compound (3.832 g, 15.2 mmol, 68% by weight).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH2:7]([NH2:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1.O>ClCCl>[Br:1][CH2:2][CH2:3][C:4]([NH:15][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:5]
Reactant: O=C(Cl)CCBr
Reactant: CCCCCCCCN
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCNC(=O)CCBr
Reaction time: 1 h
Yield: 54.3 %

Procedure:
3-Bromopropionyl chloride (25.7 g) was dissolved in dichloromethane (150 ml), cooled to -10° and a solution of octylamine (20.7 g) in dichloromethane (50 ml) was added over 10 minutes at -10° to 0°. Pyridine (12.7 g) in dichloromethane (50 ml) was added to the white suspension at -10° to 0° giving an orange solution. After stirring for 1 hour at 0°, water (100 ml) was added, the phases separated and the aqueous phase extracted with dichloromethane (2×50 ml). The combined organic extracts were washed with dilute sodium hydroxide and water, dried over MgSO4, filtered through a bed of silica gel and evaporated to give 3-bromo-N-octylpropanamide as a colourless solid (21.49 g, 54%) (mp 48°-55°).
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:17])[N:4]([CH3:18])[C:3]1=[O:19].[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:26]3[CH:27]=[CH:28][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:17])[N:4]([CH3:18])[C:3]1=[O:19]
Reactant: Cn1c(N2CCN(CCO)CC2)cc(=O)n(C)c1=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1c(N2CCN(CCOc3ccc([N+](=O)[O-])cc3)CC2)cc(=O)n(C)c1=O
Yield: 69.3 %

Procedure:
To 100 ml of anhydrous tetrahydrofuran were added 5.37 g of 1,3-dimethyl-6-[4-(2-hydroxyethyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (compound 41), 3.20 g of 4-nitrophenol and 6.03 g of triphenylphosphine, and the resulting mixture was treated in the same manner as in Example 20-(2) to obtain 5.40 g of crystalline 1,3-dimethyl-6-{4-[2-(4-nitrophenoxy)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([C:14]#[CH:15])=[CH:13][C:8]=2[C:7](=[O:16])[N:6]([CH3:17])[C:5]2[CH:18]=[CH:19][CH:20]=[N:21][C:4]1=2)[CH3:2].I[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1.N1C2C(=NC(=O)C3C=CC=NC=3N=2)C=CC=1>>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[CH:13][C:8]=2[C:7](=[O:16])[N:6]([CH3:17])[C:5]2[CH:18]=[CH:19][CH:20]=[N:21][C:4]1=2)[CH3:2]
Reactant: C#Cc1cnc2c(c1)C(=O)N(C)c1cccnc1N2CC
Reactant: COC(=O)c1ccc(I)cc1
Agent: O=c1nc2cccnc2nc2ncccc12
Product: CCN1c2ncc(CCc3ccc(C(=O)OC)cc3)cc2C(=O)N(C)c2cccnc21
Yield: 14.7 %

Procedure:
5,11-dihydro-11-ethyl-8-ethynyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.1 g, 0.36 mmol) was coupled with methyl 4-iodobenzoate (0.1 g, 0.38 mmol) by a procedure analogous to that described in Example 51b to give 79 mg of an olefinic coupled product, 5,11-Dihydro-11-ethyl-5-methyl-8-[2-(4-methoxycarbonylphenyl)ethen-1-yl]-(-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one. Hydrogenation as described in Example 56 afforded 22 mg of the title compound, m.p. 172°-173° C. (ethyl acetate/hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][N:4]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][N:4]=1
Reactant: COc1nccc(/C=C/c2ccccc2)n1
Agent: [Pd]
Solvent: CO
Product: COc1nccc(CCc2ccccc2)n1
Reaction time: 72 h
Yield: 97.2 %

Procedure:
To a solution of (E)-2-methoxy-4-styrylpyrimidine (0.51 g, 2.4 mmol) in methanol (25 mL) was added palladium on carbon (0.18 g). The reaction mixture was stirred under hydrogen balloon for 3 days and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure to provide the title compound (0.50 g, 97%) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 8.35 (d, J=5.0 Hz, 1H), 7.29-7.26 (m, 2H), 7.21-7.18 (m, 3H), 6.72 (d, J=5.0 Hz, 1H), 4.02 (s, 3H), 3.08-2.98 (m, 4H).