Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:12]([O:19][C:20](=[O:29])[CH2:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]#[N:45])=[CH:34][CH:33]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:12]([O:19][C:20](=[O:29])[CH2:21][N:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]#[N:45])=[CH:36][CH:37]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(CNc1ccccc1)OCc1ccccc1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1-c1ccc(CN(CC(=O)OCc2ccccc2)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
24.8 g (60 mmol) of rac. phenylglycine benzyl ester tosylate and 8.2 g (30 mmol) of 4-bromomethyl-2'-cyanobiphenyl are kept at 80° with stirring for 2 hours together with 15.5 g of diisopropylethylamine (Hunig base) in 60 ml of DMF. The reaction mixture is then poured into ice-water and extracted with ethyl acetate. The ethyl acetate is separated off and stirred with 2N hydrochloric acid. The hydrochloride of the title compound which precipitates as an oil is separated off, converted into the base using sodium carbonate solution and further used in crude form (Rf 0.65 in system B7).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][N:3]=1.Cl.[CH2:16]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:21][NH2:22])[CH3:17].C1CCN2C(=NCCC2)CC1>CN1CCCC1=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:18]([CH2:16][CH3:17])[CH:19]=2)=[N:4][N:3]=1
Reactant: N#Cc1ccc2c(Cl)nnc(Cl)c2c1
Reactant: CCc1cc(CN)ccc1OC
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1cc(CNc2nnc(Cl)c3ccc(C#N)cc23)ccc1OC

Procedure:
1,4-Dichlorophthalazine-6-carbonitrile and 3-ethyl-4-methoxybenzylamine hydrochloride were stirred at room temperature in 1-methyl-2-pyrrolidinone in the presence of DBU, whereby 1-chloro-4-[(3-ethyl-4-methoxybenzyl)amino]-6-phthalazine carbonitrile was obtained as a less polar compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH2:10](Br)[CH:11]=[CH2:12]>>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH:11]=[CH2:12]
Reactant: C=CCBr
Reactant: COc1ccc(O)cc1
Product: C=CCOc1ccc(OC)cc1
Yield: 98 %

Procedure:
Allyl(4-methoxyphenyl)ether was prepared in the same manner as described in Example 17A, but using 4-methoxyphenol (10 g, 84 mmol) and allyl bromide (9.7 g, 84 mmol), in 98% yield as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[CH2:34]([CH2:36][NH2:37])[OH:35].C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9]([NH:37][CH2:36][CH2:34][OH:35])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)NCCO)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Under an atmosphere of argon protective gas, 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (50 mg, 101 μmol) was dissolved in absolute THF (2.5 ml), ethanolamine (18 μl, 303 μmol; 3 eq.) and triethylamine (10.2 mg, 101 μmol; 1 eq.) were added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Kromasil C-18, 5 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (43 mg, 81% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][N:12]=[C:11]3O)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:30]>C1(C)C=CC=CC=1>[Cl:30][C:11]1[C:10]2[C:15](=[CH:16][CH:17]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: Oc1ncnc2ccc(-c3ccc(F)cc3)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Yield: 90.2 %

Procedure:
To a suspension of the product of example 7 (720 mg, 3 mmol) in toluene (20 ml) was added diisopropylethylamine (1.5 ml, 9 mmol) and POCl3 (0.84 ml, 9 mmol). The mixture was refluxed for 1 hour. The solvents were evaporated in vacuo. The residue was redissolved in dichloromethane and the organic layer was washed with ice water till pH 6-7. The combined organic layers were dried over MgSO4 and concentrated to yield the title compound as a yellow solid (700 mg, yield: 90%) which was characterized by its mass spectrum as follows: MS (m/z): 259 ([M+H]+, 100).
Reaction SMILES: C([O:9][CH2:10][C@H:11]([C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=1)[O:12][C@H:13]1[CH2:21][CH2:20][C@H:19]2[C@@H:15]([CH2:16][N:17]([C:22]3[O:23][CH2:24][C:25](=[O:27])[N:26]=3)[CH2:18]2)[C@@H:14]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])(=O)C1C=CC=CC=1.[OH-].[Na+]>CO.CCOCC>[F:47][C:45]([F:46])([F:48])[C:37]1[CH:36]=[C:35]([C@H:11]([O:12][C@H:13]2[CH2:21][CH2:20][C@H:19]3[C@@H:15]([CH2:16][N:17]([C:22]4[O:23][CH2:24][C:25](=[O:27])[N:26]=4)[CH2:18]3)[C@@H:14]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:10][OH:9])[CH:40]=[C:39]([C:41]([F:42])([F:44])[F:43])[CH:38]=1
Reactant: Cc1ccccc1[C@H]1[C@@H]2CN(C3=NC(=O)CO3)C[C@H]2CC[C@@H]1O[C@H](COC(=O)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: Cc1ccccc1[C@H]1[C@@H]2CN(C3=NC(=O)CO3)C[C@H]2CC[C@@H]1O[C@H](CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution of benzoate of Step D (4.0 g, 5.93 mmol) in 200 mL of methanol was added 6.0 mL of 2 M sodium hydroxide. The reaction mixture was maintained at ambient temperature for 1 hr, and diluted with 1200 mL ether. The organic layer was washed with 1 M sodium hydroxide (400 mL). The organic layer was then washed with water, dried over MgSO4, filtered, and concentrated to afford a white solid. The crude material was purified by flash chromatography (0-5% then 5-7% them 7% methanol in ethyl acetate. M++1: 571.2.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:18](I)([CH3:20])[CH3:19]>CN(C=O)C>[Cl:11][C:4]1[N:3]=[C:2]([F:1])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH:18]([CH3:20])[CH3:19]
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(Cl)nc(F)nc21
Reaction time: 5 h
Yield: 43.8 %

Procedure:
A mixture of 2-fluoro,6-chloro-purine (2 g, 11.7 mmol), and powdered potassium carbonate (4 g, 28 mmol) was vigorously stirred in 30 ml DMF. Isopropyliodide (6 ml, 60 mmol) was added very slowly over 2 h. The reaction was stirred for a further 5 h. DMF was removed and the crude taken up in ethyl acetate, washed with water (50 ml), brine (50 ml), dried (MgSO4) and concentrated. The crude was purified by silica gel column chromatography (30% ethyl acetate in hexane) to provide the pure product as a white solid (1.1 g, 44%). δH (CD3OD, 250 MHz) 1.65 [6 H, d, J 7.5, CH(CH3)2], 4.92 [1 H, m, CH(CH3)2], 8.66 (1 H, s, ArH); δC (CD3OD, 250 MHz) 154.7 (C), 153.88 (C), 152.2 (C), 147.65 (CH), 132.44 (C), 50.66 (CH), 22.72 (2×CH3); m/z 215.2 (M+H)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=2[CH:34]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=2[CH:34]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: O=C1COc2ccc(O)cc2N1
Product: COc1cc2c(Oc3ccc4c(c3)NC(=O)CO4)ncnc2cc1OCC1CCN(C)CC1
Yield: 87.7 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13 g, 0.4 mmol), (prepared as described for the starting material in Example 10), was reacted with 6-hydroxy-2H-4H-1,4-benzoxazin-3-one (83 mg, 0.5 mmol), (J. Chem. Soc. C, 1971, 2696), to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(3-oxo-2H-4H-1,4-benzoxazin-6-yloxy)quinazoline (158 mg, 88%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([N:12]1[C:16]([C:17]2[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][C:14]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:13]1)(=[O:11])=[O:10].C(OCC)(=O)C.[ClH:40]>C(OCC)(=O)C.CO>[ClH:40].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([N:12]1[C:16]([C:17]2[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][C:14]([CH2:24][NH:25][CH3:26])=[CH:13]1)(=[O:11])=[O:10]
Reactant: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2cc(F)ccc2F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2cc(F)ccc2F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl ({1-[(2,5-difluorophenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}methyl)methylcarbamate (160 mg) was dissolved in ethyl acetate (5 mL) and methanol (3 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) was added. The mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:9) to give the title compound as a free base. The free base was dissolved in ethyl acetate. 4 mol/L Hydrogen chloride-ethyl acetate solution was added and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 45.9 mg, 33%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]2=[O:47].O>CN(C)C=O>[CH3:46][C:38]1([N:32]2[C:31](=[O:47])[C:30]3[C:34](=[CH:35][CH:36]=[C:28]([CH2:27][NH:26][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][N:8]=4)=[O:12])[CH:29]=3)[C:33]2=[O:37])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45]
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Reactant: CCOc1ccc(C(=O)O)nc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)nc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A stirred mixture of 5-ethoxy-pyridine-2-carboxylic acid (0.33 g, 2.00 mmol) and CDI (0.36 g, 2.20 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.68 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. The solids were filtered and dissolved in CH2Cl2 (10 mL). The crude product was purified by column chromatography (0-5% MeOH/CH2Cl2, gradient, product eluted at 3% MeOH). The product fractions were combined and concentrated to give 5-ethoxy-pyridine-2-carboxylic acid[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.69 g, 77% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.98 min (95.90%); mp: 145-147° C.; 1H NMR (DMSO-d6) δ 1.37 (t, J=7.2 Hz, 3H), 1.88 (s, 3H), 2.01-2.07 (m, 1H), 2.54-2.71 (m, 3H), 4.19 (dd, J=6.9, 13.8 Hz, 2H), 4.61 (d, J=6.3 Hz, 2H), 7.53 (dd, J=3.0, 8.7 Hz, 1H), 7.77-7.82 (m, 3H), 7.99 (d, J=8.7 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 9.40 (t, J=6.3 Hz, 1H), 11.00 (s, 1H); 13C NMR (DMSO-d6) δ 12.70, 19.30, 26.90, 27.40, 40.60, 57.00, 62.40, 119.60, 120.00, 121.40, 121.70, 127.80, 129.60, 131.80, 135.10, 14.050, 145.90, 155.30, 162.30, 166.10, 166.20, 170.40, 170.50; LCMS: MH=451; Anal Calcd for C23H22N4O6+0.5H2O: C, 60.13; H, 5.05; N, 12.19. Found: C, 59.95; H, 4.91; N, 12.04.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][NH:6][CH2:5][C:4]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:3]1=2.CCN(C(C)C)C(C)C.[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36])([O-:28])=[O:27]>C(Cl)Cl>[CH3:1][C:2]1([CH3:16])[CH2:7][N:6]([S:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N+:26]([O-:28])=[O:27])(=[O:36])=[O:37])[CH2:5][C:4]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:3]1=2
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCOC(=O)c1cc2c(s1)C(C)(C)CNC2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(s1)C(C)(C)CN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C2
Temperature: 25 °C
Yield: 87.9 %

Procedure:
A solution of ethyl 7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (20.5 g, 0.074 mol) and DIPEA (42.8 g, 0.37 mol) in DCM (400 mL) was cooled to 0° C. 2-nitrobenzene-1-sulfonyl chloride (17.3 g, 0.078 mol) was then added and the reaction mixture was allowed to warm to room temperature overnight. The crude reaction solution was applied directly to a silica gel column and purified (10-20% EtOAc/hexane) to afford product (27.6 g, 88%). 1H NMR (400 MHz, CDCl3) δ 7.98 (dd, J=4.8, 2.4 Hz, 1H), 7.64-7.68 (m, 2H), 7.57 (dd, J=4.4, 2.4 Hz, 1H), 7.37 (s, 1H), 7.19 (s, 1H), 4.33 (s, 2H), 4.25 (q, J=7.2 Hz, 2H), 3.33 (s, 2H), 1.31 (s, 6H), 1.19 (t, J=7.2 Hz, 3H),
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH:4]([CH2:6][CH3:7])O.[CH2:9]([SH:22])[CH:10]([SH:21])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:11]([CH:10]1[CH2:9][S:22][C:4]([CH2:6][CH3:7])=[C:3]([CH2:2][CH3:1])[S:21]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCC(=O)C(O)CC
Reactant: CCCCCCCCCCC(S)CS
Product: CCCCCCCCCCC1CSC(CC)=C(CC)S1
Yield: 58 %

Procedure:
The method of Example 4 was followed using propioin (4-hydroxy-3-hexanone) (8.2 g) and dodecane-1,2-dithiol (15.1 g) to give 2-decyl-5,6-diethyl-2,3-dihydro-1,4-dithiin as an undistillable oil, yield 58%. NMR, (CDCl3) 0.8-1.28 δ (overlapping triplets), 1.38 δ (broadened singlet), 2.05-2.41 δ (quartet), 2.7-3.38 (multiplet).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].Cl.[CH3:28][C:29]1[CH:33]=[C:32]([NH:34][CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[NH:31][N:30]=1.C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[CH3:28][C:29]1[CH:33]=[C:32]2[N:34]([CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[C:17](=[O:18])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:22]([CH2:23][CH2:24][CH3:25])[N:31]2[N:30]=1
Reactant: Cc1cc(NC2CCOCC2)[nH]n1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2cc(C)nn12
Temperature: 180 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (0.96 g), 3-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine hydrochloride (0.3 g) and N,N-diethylaniline (10 mL) was stirred at 180° C. for 2 hr. The obtained reaction mixture was diluted with ethyl acetate, washed 3 times with 1 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.27 g, 42%).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH3:19])[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH:19]=[CH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1
Reactant: C#CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C#CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 31 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-prop-2-ynyloxy-8-acetylcoumarin (1.92 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized by ethanol to give 0.8 g of product m.p. 140-42° C., 1H-NMR (CDCl3) δ: 2.45 (s, 3H); 2.53-2.56 (m, 1H); 4.82 (d, 2H, J=2.2 Hz); 6.20 (s, 1H); 7.02 (d, 1H, J=16 Hz); 7;13 (d, 1H, J−=8.9 Hz); 7.32 (d, 1H, J=16 Hz); 7.35-7.45 (m, 3H); 7.48-7.52 (m, 2H); 7.67 (d, 1H, J=8.9 Hz).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].C([Li])CCC.CCCCCC.Cl[Si](C)(C)C.[CH3:23][C:24](=[O:26])[CH3:25]>O1CCCC1>[NH2:6][C:2]1[S:1][C:5]([C:24]([OH:26])([CH3:25])[CH3:23])=[CH:4][N:3]=1
Reactant: Nc1nccs1
Reactant: CC(C)=O
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(O)c1cnc(N)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution of thiazol-2-amine (7.0 g, 69.9 mmol) in tetrahydrofuran (200 mL) was added a 10.0 M solution of butyllithium in hexane (14 mL, 140 mmol). The mixture was stirred at −78° C. for 1 hour and chlorotrimethylsilane (15.2 g, 140 mmol) was added dropwise. The mixture was allowed to warm up to −40° C., cooled to −78° C. and a 10.0 M solution of butyllithium in hexane (7.0, 70 mmol) was added. After 10 minutes, propan-2-one (8.12 g, 140 mmol) was added and the mixture was stirred for 12 hours. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ether. The organic extract was dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.61 (s, 6H) 5.04-5.19 (brs, 2H) 6.89 (s, 1H); MS (ESI) m/z 159 (M+H)+.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][N+:15]([O-])=[C:14]([CH3:19])[C:13]=1[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:21]([O:24]C(=O)C)(=[O:23])[CH3:22]>>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:19][O:24][C:21](=[O:23])[CH3:22])[C:13]=1[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCOc1cc[n+]([O-])c(C)c1C
Product: CCCCCCCCCCOc1ccnc(COC(C)=O)c1C
Yield: 61.6 %

Procedure:
To 41.2 g (0.1 mol, 1.0 eq.) of 4-decyloxy-2,3-dimethylpyridine-N-oxide, 40.8 g (0.4 mol, 4.0 eq.) of acetic anhydride was added, and the mixture was allowed to react for 8.5 hours at 88 to 92° C. Acetic anhydride was distilled off, and then the resulting concentrated residue was purified on a silica gel column, to obtain 19.8 g of 4-decyloxy-2-acetoxymethyl-3-methylpyridine as a black brown oily matter (total yield of two processes 61.7%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH2:16][NH2:17])[C:10]=2[N:9]=[CH:8]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:30]=[C:29]([CH:31]3[CH2:33][CH2:32]3)[NH:28][N:27]=2)[C:22]([F:34])=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:31]1([C:29]2[CH:30]=[C:26]([NH:25][C:23]3[C:22]([F:34])=[CH:21][N:20]=[C:19]([NH:17][CH2:16][C:15]4[C:10]5[N:9]=[CH:8][N:7]([CH:2]6[CH2:3][CH2:4][CH2:5][CH2:6][O:1]6)[C:11]=5[CH:12]=[CH:13][CH:14]=4)[N:24]=3)[NH:27][N:28]=2)[CH2:33][CH2:32]1
Reactant: NCc1cccc2c1ncn2C1CCCCO1
Reactant: Fc1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1cnc(NCc2cccc3c2ncn3C2CCCCO2)nc1Nc1cc(C2CC2)n[nH]1
Temperature: 120 °C
Yield: 56.7 %

Procedure:
A tube was charged with 58 (273 mg, 1.18 mmol), 55 (150 mg, 0.59 mmol), DIPEA (0.5 ml) and IPA (4 mL), degassed, sealed and heated at 120° C. for 72 h. The solvent was evaporated in vacuo to afford 150 mg (57%) of N4-(3-cyclopropyl-1H-pyrazol-5-yl)-5-fluoro-N2-((1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-4-yl)methyl)pyrimidine-2,4-diamine (280)—as yellow solid: MS (ESI) m/z=449.7 [M+1]+.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:37]2[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=2)O1.C(O)C>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.C1(C)C=CC=CC=1>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:37]3[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=3)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: CC1(C)OB(c2ccc(C#N)cc2)OC1(C)C
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3ccc(C#N)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
A flask was charged with 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (200 mg, 0.542 mmol), potassium carbonate (150 mg, 1.083 mmol), tetrakis(triphenylphosphine)palladium(0) (6.26 mg, 5.42 μmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (149 mg, 0.650 mmol) then filled with ethanol (2 mL) and toluene (2 mL) and the resulting mixture was stirred under nitrogen at 90° C. for 16 h then cooled to room temperature and partitioned between water (20 mL) and EtOAc (60 mL). The layers were separated and the aqueous phase was extracted with EtOAc (30 mL). The combined organic phases were washed with brine (30 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 10 to 55% AcOEt in hexanes) gave 1-methylethyl[(2S,4R)-1-acetyl-6-(4-cyanophenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (176 mg, 0.45 mmol, 83%) as a white solid. LCMS (method G): Retention time 1.03 min, [M+H]+=392.0