Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:17][Mg]Br.O>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[OH:1][CH:2]([CH3:17])[CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(O)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 250 mg of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate in 5 mL of THF was added 1.2 mL of 1.4M methyl magnesium bromide in toluene-THF, followed by stirring at room temperature for 2 hours. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-10:1] to obtain 236 mg of tert-butyl 4-(2-hydroxypropyl)piperidine-1-carboxylate as a colorless oily substance.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([NH2:11])[CH2:8][CH2:7][C@@H:6]1[N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]1=[O:28])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:36][O:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=1.[BH4-].[Na+]>CO.C([O-])(O)=O.[Na+].CCOC(C)=O>[C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([NH:11][CH2:42][C:41]2[CH:44]=[CH:45][C:38]([O:37][CH3:36])=[CH:39][CH:40]=2)[CH2:8][CH2:7][C@@H:6]1[N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:13]1=[O:28])(=[O:3])[CH3:2]
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)N[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN[C@@H]2CC[C@H](N3CC[C@H](NC(=O)OCc4ccccc4)C3=O)[C@H](NC(C)=O)C2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.6 %

Procedure:
A sample of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-aminocyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (34.8 g, ca. 90 mmol) was dissolved in methanol (400 ml). The flask was purged with nitrogen and charged with triethylamine (15.61 ml, 112 mmol), followed by 4-methoxybenzaldehyde (13.62 ml, 112 mmol). The reaction was stirred at RT for 14 h, at which time LC/MS of reaction showed complete consumption of primary amine and formation of desired imine (LC/MS found [M+H]+=507.4). The reaction was cooled to 0° C. and charged with sodium borohydride (5.08 g, 134 mmol) in portions over 1 minute. The ice bath was removed after 30 min and the solution stirred for an additional 3.5 h. The reaction was concentrated in vacuo to give a white solid/gum, which was dissolved in 400 mL sat. NaHCO3 and 1200 mL EtOAc. The phases were mixed vigorously and then separated. The organic phase was washed 2×800 mL 0.5N HCl (note: a small third, oily phase was on the bottom in the first extraction; took along with the acid phase). The acid washes were combined, basified with solid NaOH to pH 13, cooled to RT, and then extracted with EtOAc (1×1000 mL; 2×600 mL). The organic extracts were combined, washed with brine (1×120 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was dissolved in dichlormethane and concentrated; this procedure was repeated to give benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(4-methoxybenzylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (43.68 g, 86 mmol, 96% yield) as a flowing microcrystalline solid after pumping on high vacuum. LC/MS found [M+H]+=509.6.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[O:12]1[C:16]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+].CN(C)C=O>O.CCOCC>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[N:19]1[CH2:20][CH2:21][C:16]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:17][CH2:18]1
Reactant: Clc1ccc2ccccc2n1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: c1ccc2nc(N3CCC4(CC3)OCCO4)ccc2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 21.8 %

Procedure:
A mixture of 10 g (0.0613) of 2-chloroquinoline, 27 g (0.1886 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, 13 g (0.0941) of K2CO3, and 75 ml of dimethylformamide is stirred at 100°-110° C. for 4 days. The reaction mixture is allowed to cool to ambient temperature, diluted with water and extracted with ethyl acetate. The combined organic extracts are washed copiously with water, then brine, dried over Na2SO4, and concentrated in vacuo to give a waxy solid. Trituration with ether furnishes 3.6 g (22%) of title compound: IR (KBr) 1620, 1610, and 1510 cm-1 ; NMR (CDCl3) δ 7.92 (d, 1H), 7.78-7.50 (m, 3H), 7.30-7.22 (m, 1H), 7.04 (d, 1H), 4.02 (s, 4H), 3.94-3.86 (m, 4H), and 1.88-1.76 (m, 4H).
Reaction SMILES: C[O:2][C:3]1[C:11]2[C:7](=[N:8][C:9](=[O:12])[N:10]=2)[C:6]([CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[CH:5][CH:4]=1.B(Br)(Br)[Br:23]>C(Cl)Cl>[BrH:23].[OH:2][C:3]1[C:11]2[C:7](=[N:8][C:9](=[O:12])[N:10]=2)[C:6]([CH2:13][CH2:14][N:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])=[CH:5][CH:4]=1
Reactant: CCCN(CCC)CCc1ccc(OC)c2c1=NC(=O)N=2
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Br
Product: CCCN(CCC)CCc1ccc(O)c2c1=NC(=O)N=2
Reaction time: 4 h
Yield: 86 %

Procedure:
A mixture of 1.83 g (0.00629 m) of 4-methoxy-7-[2-(N,N-di-n-propylamino)ethyl]-1,3-benzimidazol-2-one in 100 ml of methylene chloride was cooled to -30° while 17.5 ml of 1M boron tribromide in methylene chloride was added dropwise. After standing at room temperature for 4 hours, the mixture yielded an oil which solidified. The residue was triturated with methanol, then recrystallized from isopropanol to give 1.94 g (86%) of 4-hydroxy-7-[2-(N,N-di-n-propylamino)ethyl]-1,3-benzimidazol-2-one hydrobromide; 240°-242°.
Reaction SMILES: C[O-].[Na+].[CH2:4]([O:6][C:7](=[O:17])[C:8](CC)(CC)P(O)(O)=O)C.[CH2:18](/[C:20](=[CH:23]\[CH2:24][CH3:25])/[CH:21]=O)[CH3:19].O>CO>[CH2:18](/[C:20](=[CH:23]\[CH2:24][CH3:25])/[CH:21]=[CH:8]/[C:7]([O:6][CH3:4])=[O:17])[CH3:19]
Reactant: CC/C=C(/C=O)CC
Reactant: CCOC(=O)C(CC)(CC)P(=O)(O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC/C=C(/C=C/C(=O)OC)CC
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
To a 28 wt % solution of sodium methoxide in methanol (25.7 g) at 10° C. were added dropwise diethyl phosphonoacetic acid ethyl ester (25.3 g) and (E)-2-ethyl-2-pentenal (11.5 g) successively under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 hours, poured into chilled water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (dichloromethane) to give 13.4 g of methyl (E,E)-4-ethyl-2,4-heptadienoate as an oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][C@H:4]([OH:26])[C@@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C@@H:17]([CH3:20])[CH2:18][CH3:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:34][C@@H:35]([CH2:54][CH3:55])[C@H:36]([N:40]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[N:47]=2)[C:41]1=[O:53])[C:37](O)=[O:38].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:6]([C@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[CH:17]([CH3:20])[CH2:18][CH3:19])=[O:15])[C@@H:4]([OH:26])[CH2:3][C@@H:2]([NH:1][C:37](=[O:38])[C@@H:36]([N:40]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[N:47]=2)[C:41]1=[O:53])[CH:35]([CH3:34])[CH2:54][CH3:55])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccc(C)n2)C1=O
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](N)Cc1ccccc1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)CC)N1CCN(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
A solution containing the product from Example 9B (0.36 g, 0.79 mmol) in THF (8 mL) was treated with the product from Example 7B (0.33 g, 0.79 mmol), DEPBT (0.355 g, 1.19 mmol), and N,N-diisopropylethylamine (0.70 mL, 4.02 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-50% acetone/dichloromethane to give the title compound (0.264 g, 45% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.75 (m, 12 H), 0.94 (m, 2 H), 1.29 (m, 2 H), 1.46 (m, 2 H), 1.62 (m, 1 H), 1.80 (m, 1 H), 2.43 (m, 4 H), 2.68 (m, 3 H), 2.88 (m, 1 H), 3.08 (m, 3 H), 3.56 (m, 4 H), 3.84 (m, 2 H), 4.15 (m, 2 H), 4.34 (s, 2 H), 4.84 (d, J=5.88 Hz, 1 H), 7.03 (m, 7 H), 7.15 (m, 6 H), 7.39 (d, J=9.19 Hz, 1 H), 7.66 (t, J=7.72 Hz, 1 H), 7.83 (d, J=8.82 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][N:13]3[CH:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]4[C:23]([CH3:37])=[CH:24][C:25]([NH:29]C(=O)OC(C)(C)C)=[N:26][C:27]=4[CH3:28])=[O:19])[CH:15]=[N:14]3)=[N:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][C:25]1[N:26]=[C:27]([CH3:28])[C:22]([CH2:21][NH:20][C:18]([C:16]2[CH:15]=[N:14][N:13]([CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[CH:17]=2)=[O:19])=[C:23]([CH3:37])[CH:24]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc3ccc(Cl)cc3n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N)nc(C)c1CNC(=O)c1cnn(Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 23 °C
Reaction time: 7.5 h

Procedure:
To a solution of tert-butyl (5-((1-((7-chloroquinolin-2-yl)methyl)-1H-pyrazole-4-carboxamido)methyl)-4,6-dimethylpyridin-2-yl)carbamate (151 mg, 0.29 mmol) in DCM (2 ml) was added TFA (0.447 ml, 5.80 mmol). Reaction mixture was stirred for 7.5 h at 23° C. After evaporation of solvents, the crude material was purified by preparative HPLC (SunFire C18-ODB, 5 μm, 100×30 mm, elution with A=water+0.1% TFA and B=ACN+0.1% TFA, gradient from 5% to 100% B in 25 min, flow: 40 mL/min). Fractions were combined, and the solvents were evaporated to afford the title cpd as a TFA salt, which was dissolved in hot methanol/ACN and eluted through a PL-HCO3 MP-resin column (Stratosphere SPE) in order to remove salt. The eluted solution was evaporated, and the residue was dried over a weekend under high vacuum (dessicator, 50° C.) to afford the title compound as a free base. 1H-NMR (DMSO-d6, 400 MHz) δ 8.40 (d, 1H), 8.38 (s, 1H), 8.03 (s, 1H), 8.02 (d, 1H), 7.94 (broad s, 2H), 7.65 (d, 1H), 7.24 (d, 1H), 6.11 (s, 1H), 5.63 (s, 2H), 5.61 (broad s, 2H), 4.28 (d, 2H), 2.29 (s, 3H), 2.16 (s, 3H); HPLC (Method G) Rt=1.476 min, MS (Method V) [M+H]+=422.3.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:36].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C@@H:17]([OH:36])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: [OH-]
Reactant: COc1cc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)cc(OC)c1OC
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc(OC)c1OC

Procedure:
In analogy with Example 44d), 1.097 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(3,4,5-trimethoxyphenyl)methyl]dihydrofuran-2-(3H)-one in 36.48 ml of dimethoxyethane and 18.39 ml of water are hydrolysed with 9.03 ml of 1M lithium hydroxide solution to give the title compound, which is subjected, without purification, to further processing.
Reaction SMILES: C[O-].[Na+].[N+:4]([CH:7]=[C:8](SC)[S:9]([CH3:11])=O)([O-:6])=[O:5].Br.[Br:15][CH2:16][CH2:17][NH2:18]>CO>[N+:4]([CH:7]=[C:8]([S:9][CH3:11])[NH:18][CH2:17][CH2:16][Br:15])([O-:6])=[O:5]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: NCCBr
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSC(=C[N+](=O)[O-])NCCBr
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
(b)(i) A solution of sodium methoxide (sodium (0.3 g, 0.013 mol) in methanol (10 ml)) was added dropwise, over a period of 10 minutes to a stirred mixture of 1-nitro-2-methylthio-2-methylsulphinylethylene (2 g, 0.011 mol) and 2-bromoethylamine hydrobromide (2.7 g, 0.013 mol) in methanol (25 ml), cooled to 0°. The solution was stirred at 0° for a further 15 minutes, and then it was allowed to attain room temperature. After 1 hour, the solvent was removed in vacuo, and the semi-solid residue was extracted with hot chloroform (2×25 ml). The extracts were combined and concentrated in vacuo. The solid residue was recrystallised from propan-2-ol to give 1-nitro-2-methylthio-2-(2-bromo-ethylamino)ethylene (1.85 g, 71%) m.p. 123°14 126°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]Br)([CH3:4])([CH3:3])[CH3:2].[C:12]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[OH:24])#[N:13].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:21][O:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][C:14]([C:12]#[N:13])=[C:15]([O:24][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11])[CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COC(=O)c1ccc(C#N)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)c(OCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2-Bromoethyl)carbamic acid tert-butyl ester (700 mg, 3.12 mmol) from step 1 and 4-cyano-3-hydroxybenzoic acid methyl ester (Example 34 Step 3, 550 mg, 3.12 mmol) was dissolved in DMF (4.5 ml). Cs2CO3 (2.03 g, 6.24 mmol) was added and the reaction stirred at room temperature for 2 hours. The reaction mixture was filtered through celite and washed with DMF (3×10 mL). The DMF was removed in vacuo. The residue was purified by flash chromatography (12% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: S(Cl)(Cl)=O.[O:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1.[CH3:14][Si](C=[N+]=[N-])(C)C.[BrH:21]>C(O)(=O)C>[Br:21][CH2:14][C:11]([CH:8]1[CH2:7][CH2:6][O:5][CH2:10][CH2:9]1)=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Br
Reactant: O=C(O)C1CCOCC1
Solvent: CC(=O)O
Solvent: O=S(Cl)Cl
Product: O=C(CBr)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
Thionyl chloride (2 mL, 27 mmol) was added to tetrahydro-pyran-4-carboxylic acid (1.1 g, 8.4 mmol) at 10° C. The mixture was warmed to ambient temperature and stirred for 2 h. Excess thionyl chloride was evaporated and the residue co-distilled with toluene to remove the traces of thionyl chloride. The resulting crude acid chloride was dissolved in dry acetonitrile (3 mL) and cooled to 0° C. Trimethylsilyl diazomethane (12.6 mL, 25.3 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 h. It was then cooled to −10° C. and a solution of 15% HBr in acetic acid (2 mL) was added. The mixture was stirred at room temperature for 1 h then quenched with saturated sodium bicarbonate solution and extracted with ether (3×20 mL). The combined ether extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-bromo-1-(tetrahydro-pyran-4-yl)-ethanone (620 mg, 35%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[C:9](=[CH:12][N:13]3[CH2:18]COCC3)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+:19]([O-])(O)=O.[C:23]1([NH:29]C(N)=N)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>COCCO>[CH3:1][C:2]1[S:3][C:4]2[C:10]3[N:19]=[C:18]([NH:29][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:13]=[CH:12][C:9]=3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: N=C(N)Nc1ccccc1
Reactant: Cc1nc2c(s1)C(=O)C(=CN1CCOCC1)CC2
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: Cc1nc2c(s1)-c1nc(Nc3ccccc3)ncc1CC2
Temperature: 100 °C
Yield: 47.6 %

Procedure:
A mixture of 2-methyl-6-morpholin-4-ylmethylene-5,6-dihydro-4H-benzothiazol-7-one (300 mg, 1.1 mmol), N-phenyl-guanidine nitrate (449 mg, 2.3 mmol), NaOH (109 mg, 2.7 mmol) and 2-methoxyethanol (5 mL) was heated at 100° C. for 8 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (20% EtOAc hexane) followed by crystallisation from EtOH afforded the title product as a white solid (154 mg, 46%): mp 223-224° C. Anal. RP-HPLC: tR 17.1 min (0-60% MeCN, purity 100%). 1H-NMR (CDCl3): δ 8.19 (s, 1H, Py-H), 7.64 (d, 2H, J 7.4, Ph-H), 7.33 (t, 2H, J 7.4, Ph-H), 7.27 (brs, 1H, NH), 7.02 (t, 1H, J 7.4, Ph-H), 3.02 (m, 4H, CH2—CH2), 2.76 (s, 3H, CH3). 13C-NMR (CDCl3): δ 169.47, 159.20, 159.10, 157.05, 155.22, 139.82, 128.96, 128.84, 122.22, 118.89, 116.57, 25.38, 24.03, 19.93. MS (ESI+): m/z 295.08 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl>O1CCCC1>[CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNC(=O)c1ccc(CCCC)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCNCc1ccc(CCCC)cc1

Procedure:
A solution of 38.0 g of N-heptyl-4-n-butylbenzamide and 280 ml of borane-tetrahydrofuran complex in 120 ml of anhydrous tetrahydrofuran was refluxed for 18 hours, allowed to cool, and treated with 6N hydrochloric acid. The organic solvent was evaporated and the residue was partitioned between ether and aqueous sodium hydroxide solution. The ether layer was separated, dried, and evaporated. The residue was distilled to yield N-heptyl-4-n-butylbenzenemethanamine as a colorless liquid, bp 115° C. at 80μ.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:20]([O:22]C)=[O:21])=[CH:10][C:11]([CH:18]=[CH2:19])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].O.Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:20]([OH:22])=[O:21])=[CH:10][C:11]([CH:18]=[CH2:19])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1cc(C(=O)OC)c(-c2cccc(F)c2)c2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=Cc1cc(C(=O)O)c(-c2cccc(F)c2)c2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 8-(3-fluorophenyl)-5-vinylquinoline-7-carboxylate (0.069 g, 0.22 mmol) and 1.0 M sodium hydroxide in water (2 mL, 2 mmol) in methanol (2 mL) was stirred at room temperature overnight. After acidified with 1 N HCl, the mixture was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated to dryness. The crude acid was used directly in the next step (66 mg, 100%). LCMS calculated for C18H13FNO2 (M+H)+: m/z=294.1; Found: 294.0.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH2:9]([O:13][C:14](=[O:17])[CH:15]=[CH2:16])[CH2:10][CH2:11][CH3:12]>>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1/[CH:16]=[CH:15]/[C:14]([O:13][CH2:9][CH2:10][CH2:11][CH3:12])=[O:17]
Reactant: Cc1ccccc1I
Reactant: C=CC(=O)OCCCC
Product: CCCCOC(=O)/C=C/c1ccccc1C

Procedure:
2-Iodotoluene (32 μL, 0.25 mmol) and n-butylacrylate (54 μL, 0.375 mmol) were coupled using the procedure described above to give 83% conversion to (E)-n-butyl 3-(2-methylphenyl)acrylate by GC analysis.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)[CH:14]=[O:15]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[CH:10]=[CH:9][N:8]([CH2:2][C@H:1]2[CH2:5][CH2:6][CH2:14][O:15]2)[C:7](=[NH:11])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccnc(N)c1
Reactant: CN(C)C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Product: CC(C)(C)c1ccn(C[C@H]2CCCO2)c(=N)c1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
A mixture of 4-tert-butylpyridin-2-amine (1.0 g, 6.7 mmol, LeadGen Labs), Example 11A (2.0 g, 8.0 mmol), and tetrabutylammonium iodide (1.2 g, 3.3 mmol) in N,N-dimethylformamide (1.3 mL) was heated at 95° C. for 16 h. The reaction was incomplete as monitored by LC/MS. One more equivalent of both Example 11A and tetrabutylammonium iodide were added. After stirring at 95° C. for 16 h, the reaction mixture was cooled and quenched with saturated NaHCO3 (10 mL). The aqueous layer was extracted with dichloromethane (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 235 (M+H)+.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][N:9]([CH3:11])[NH2:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[C:1]1(=[N:10][N:9]([CH3:11])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)N
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CN(C)N=C1CCCCC1
Temperature: 70 °C
Reaction time: 72 h
Yield: 87.4 %

Procedure:
To solution of cyclohexanone (2.00 g, 20.4 mmol) and N,N-dimethylhydrazine (1.50 ml, 20.4 mmol) in ethanol (20 ml) was added a catalytic amount of toluene-4-sulfonic acid monohydrate. The reaction mixture was stirred at 70° C. for 72 h. The solvent was evaporated, and the residue was purified by Kugelrohr distillation (60-80° C., 5 mbar) to give the title compound (2.50 g, 87%) as colorless oil. MS m/e: 141 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:15][CH:16]=2)[NH:11][C:10]1=[O:23].[H-].[Na+].Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1CCl.[CH3:35]N(C)C=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:15][CH:16]=2)[N:11]([CH2:35][C:31]2[CH:32]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:10]1=[O:23]
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)c1ncc2c(n1)NC(=O)N(c1c(Cl)cccc1Cl)C2
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)c1ncc2c(n1)N(Cc1cccnc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Temperature: 100 °C
Yield: 48 %

Procedure:
An ice-cooled solution of 100 mg (0.27 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one in 6 ml of dimethylformamide was treated with 22 mg (0.54 mmol) of sodium hydride (60% w/w). After 30 minutes the mixture was treated with 50 mg (0.3 mmol) of picolyl chloride hydrochloride and then heated to 90° C. for 2 hours and to 100° C. for a further hour. The mixture was evaporated and the residue was treated with 30 ml of dichloromethane and 30 ml of water. The phases were separated and the organic phase was washed with 30 ml of water, dried over magnesium sulfate, filtered and evaporated to give 60 mg (48%) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydro-1-[(3-pyridyl)methyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a yellow solid.