Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[N:11]=[C:12](SC)[NH:13][CH:14]=2)=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=2)=[CH:21][C:20]=1[C:35]([F:38])([F:37])[F:36]>C(O)C>[Cl:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:12]3[NH:13][CH:14]=[C:9]([CH2:8][C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=4)[C:10](=[O:17])[N:11]=3)=[CH:26][CH:25]=2)=[CH:21][C:20]=1[C:35]([F:36])([F:37])[F:38]
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CSc1nc(=O)c(Cc2cnc(C)nc2)c[nH]1
Solvent: CCO
Product: Cc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Yield: 69.5 %

Procedure:
5-(2-Methyl-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (30 mg, 248.31 gmol−1, 0.12 mmol, 1 eq) and 2-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (57 mg, 315.73 gmol−1 0.18 mmol, 1.5 eq) were stirred in 300 μl of absolute ethanol at 125° C. for 50 hours. Solvent from the reaction mixture was evaporated and the resulting crude was purified by preparative HPLC-MS. The gathered fractions of appropriate composition were lyophilized and the resulting oily product was triturated with DCM and diethyl ether to afford 2-{2-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamino}-5-(2-methyl-pyrimidin-5-ylmethyl)-1H-pyrimidin-4-one (43 mg, yield=65.5%, purity=95%) MS: [M+H]+=516.38. 1H NMR (300 MHz; CDCl3) δ/ppm 2.64 (s, 3H), 2.89 (t, J=7.0 Hz, 2H), 3.52 (s, 2H), 3.57-3.66 (m, 2H), 5.20 (br.s., 1H), 6.94 (d, J=7.75 Hz, 2H), 7.02 (d, J=9.26 Hz, 1H), 7.17-7.30 (m, 3H), 7.39 (d, J=8.70 Hz, 1H), 7.67 (s, 1H), 8.49 (s, 2H), 12.18 (br.s., 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][CH3:10])[N:4]=[CH:3]1.[C:11]([O:19]CC)(=O)[CH2:12][C:13]([O:15]CC)=O.C1(OC2C=CC=CC=2)C=CC=CC=1.CN1CCCC1=O>>[OH:19][C:11]1[C:12]2[C:13](=[O:15])[N:9]([CH3:10])[CH:5]=[N:4][C:3]=2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=1
Reactant: CNc1cc(=O)n(C)cn1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: Cn1cnc2c(c(O)cc(=O)n2C)c1=O
Reaction time: 0.5 h

Procedure:
3-Methyl-6-(methylamino)pyrimidin-4(3H)-one (compound 1B; 400 mg, 2.88 mmol, 1 eq), diethyl malonate (873 μl, 5.76 mmol, 2 eq) and phenyl ether (915 μl, 5.76 mmol, 2 eq) were dissolved in 1-methyl-2-pyrrolidinone (2 ml, 20 mmol). The mixture was placed in a microwave reactor at 240° C. for 30 minutes to yield 5-hydroxy-3,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (compound 1C). The product was confirmed by LC-MS and isolated by HPLC to give 125 mg (21%) of compound 1C. [M+H] calc'd for C9H9N3O3, 208. found, 208.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1.C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:11][C:5]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:4]=1[N:1]1[C:21]([NH2:22])=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[N:3]=[N:2]1
Reactant: COc1ccc(CC#N)cc1
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-c2nnn(-c3ccc(Cl)cc3Cl)c2N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To an ice-cooled and stirred mixture of 1-azido-2,4-dichloro-benzene (0.400 g, 1 eq) and commercial (4-methoxy-phenyl)-acetonitrile (0.376 g, 1.2 eq) in ethanol (3 ml) kept under nitrogen, a solution of sodium methoxide (0.172 g, 1.5 eq) in ethanol (2 ml) is added drop-wise (15 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (25 ml), washed with water (2×25 ml), dried over MgSO4 and evaporated to dryness. The yellow semisolid residue (0.750 g) is purified by crystallization from a mixture of dichloromethane and hexane (1:1), to afford the title compound as white solid (0.315 g, 44% yield). M.p. 149.2-150.7° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24]([CH3:29])([CH3:28])[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:34]([C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:34]([C:38]1[CH:39]=[CH:40][C:41]([CH2:42][N:18]([CH2:17][C:16]2[CH:32]=[CH:33][C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=3)=[CH:14][CH:15]=2)[C:19]2[CH:31]=[CH:30][C:22]3[O:23][C:24]([CH3:29])([CH3:28])[O:25][C:26](=[O:27])[C:21]=3[CH:20]=2)=[CH:44][CH:45]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(C(C)(C)C)cc3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.6 %

Procedure:
To a solution of 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one (150 mg, 0.34 mmol) in anhydrous DCE (3 mL) were added 4-tert-butylbenzaldehyde (Aldrich, 85 μL, 0.51 mmol) and sodium triacetoxyborohydride (110 mg, 0.51 mmol). The reaction mixture was stirred at rt for 72 hrs. The solvent was removed under reduced pressure. The residue was taken up with an aqueous solution of NaOH (2 mL, 1N) and extracted with Et2O (6 ml). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. Purification by flash chromatography on silicagel (pentane/DCM (2/3)) gave 71 mg (31%) of the title compound as a yellow oil. HPLC, Rt: 6.4 min (purity: 86.3%). 1H NMR (CDCl3) δ: 7.85-6.90 (m, 15H), 4.62 (brs, 4H), 2.62 (t, J=7.6 Hz, 2H), 1.70 (s, 6H), 1.61 (m, 2H), 1.33 (m, 2H), 1.30 (s, 9H), 0.93 (t, J=7.2 Hz, 3H).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].C(O)(=O)C(O)=O.[CH2:31]([NH:33][NH2:34])[CH3:32].C(OCC)C>C(O)(=O)C>[CH2:31]([N:33]1[C:9]([CH2:10][CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[CH:8][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:34]1)[CH3:32]
Reactant: CCNN
Reactant: CCOC(=O)C(=O)CC(=O)CCN1C(=O)c2ccccc2C1=O
Agent: O=C(O)C(=O)O
Agent: [Na]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CCN2C(=O)c3ccccc3C2=O)n(CC)n1
Reaction time: 2 h

Procedure:
A modification of the method described in Part A of Example 11 was followed. A solution of ethyl 2,4-dioxo-6-phthalimidohexanoate, sodium salt (37.64 g, 0.110 mol) in glacial acetic acid (160 L) was cooled to 10° C. before the addition of ethylhydrazine oxalate (16.52 g, 0.110 mol). During the addition, the reaction temperature was maintained between 9 and 11° C. The reaction was complete in two hours. The crude product, a reddish-orange oil, was treated with diethyl ether (150 mL) to form a solid, which was isolated by filtration to provide 26.5 g of ethyl 1-ethyl-5-(2-phthalimidoethyl)-1H-pyrazole-3-carboxylate as a tan solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(O[N:55]1N=N[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC=CC=1CN>CN1C(=O)CCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C:32](=[O:33])[CH2:61][C:60]5[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=5)=[CH:35][CH:36]=4)=[O:37])=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1ccccn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)Cc2ccccn2)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 15.7 %

Procedure:
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with pyridin-2-ylmethanamine (43 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (9 mg, 15% yield); MS (ESI) m/z=596.6.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[N:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.CO>O1CCCC1>[NH:20]1[CH:24]=[C:23]([C:25]2[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[N:21]1
Reactant: Nc1ncccc1-c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ncccc1-c1cn[nH]c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
3-(1-Trityl-1H-pyrazol-4-yl)-pyridin-2-ylamine (2.3 g, 5.71 mmol) described in Manufacturing Example 32-1-3, 2 N hydrochloric acid (15 mL), methanol (15 mL) and tetrahydrofuran (10 mL) were stirred for 30 minutes at 70° C. The reaction solution was allowed to room temperature, and partitioned into water and ethyl acetate. Saturated sodium bicarbonate solution was added to the separated aqueous layer, which was then extracted with ethyl acetate 6 times. The ethyl acetate layers were combined and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate, then ethyl acetate:methanol=10:1) to obtain the title compound (625 mg, 68.3%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2ccc(Br)cc2)nc2cccnc21)Nc1ccccc1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (2.6 g, 0.020 mole) was added dropwise (slowly) to a stirred and chilled (5°-10° C.) suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.4 g, 0.019 mole) in anhydrous dimethylformamide (50 ml). The reaction mixture was heated at 55°-60° C. for 5 hours, cooled to room temperature, and added dropwise to a stirred and chilled (10°-15° C.) solution of aniline (1.9 g, 0.020 mole) and triethylamine (2.1 g, 0.020 mole) in anhydrous dimethylformamide (100 ml). The reaction mixture was stirred at room temperature overnight, filtered, and poured into ice water (500 ml). The mixture was allowed to precipitate and was filtered. The filter cake was triturated in potassium bicarbonate solution (100 ml), filtered, and the cake washed with water (100 ml). Recrystallization from tetrahydrofuran-isopropyl ether and then isopropyl alcohol-ethanol-tetrahydrofuran give 3.8 g (49%) of an off-white solid, mp 242°-243.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:7]([Cl:12])=[N:8][CH:9]=[N:10][CH:11]=1)[CH3:2].[CH:14]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[Cl:12][C:7]1[C:6]([CH:5]([CH3:14])[C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:11][N:10]=[CH:9][N:8]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)Cc1cncnc1Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1cncnc1Cl
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
To a stirred, cooled (−78° C. solution of 5.8 g (29 mmol) of ethyl(4-chloro-5-pyrimidinyl)acetate (see Step A, i-20) in 75 mL of anhydrous THF under an atmosphere of nitrogen was added 15.2 mL (30.4 mmol) of a 2.0 M solution of lithium diisopropylamide in anhydrous THF. The resulting mixture was stirred for 15 min then 2.26 mL (36.1 mmol) of iodomethane was added over 5 min. The reaction mixture was stirred for 15 min, allowed to warm to −20° C. over 45 min, then warmed to 0° C. for 15 min. The reaction mixture was then quenched with a saturated ammonium chloride solution and extracted with 50 mL of dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude residue was purified by silica gel chromatography eluting with a 20% ethyl acetate in hexanes mixture afforded the title compound (1.9 g, 31%). 1H-NMR (500 MHz, CD3OD) δ: 8.88 (s 1H), 8.74 (s, 1H), 4.17 (m, 2H), 1.58 (d, J=7 Hz, 3H), 1.29 (t, J=7 Hz, 3H). LC-MS: m/z (E/S) 215 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.CCN(CC)CC.[C:24]([O:28][C:29]([NH:31][C@H:32]([C:36](O)=[O:37])[CH:33]([CH3:35])[CH3:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:36](=[O:37])[C@H:32]([CH:33]([CH3:34])[CH3:35])[NH:31][C:29]([O:28][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:30])[CH2:4][CH2:5]2)=[CH:15][CH:14]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.8 %

Procedure:
A solution of 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine (1.0 g, 4.2 mmol) in CH2Cl2 (21 mL) was treated with Et3N (0.76 mL, 5.44 mmol), dl-N-(tert-butoxycarbonyl)valine (1.09 g, 5.03 mmol), EDCI (883 mg, 4.61 mmol) and HOBt (623 mg, 4.61 mmol). The reaction mixture was stirred at 25° C. for 16 h. The resulting solution was diluted with CH2Cl2 (20 mL), and washed with 2 N NaOH solution (2×20 mL), brine (1×20 mL) and dried (MgSO4). Concentration and chromatography (SiO2, 3% CH3OH/CH2Cl2) afforded 1-(4-chlorobenzyl)-4-[{(N-Boc-valyl)amino}methyl]piperidine (1.1 g, 60%) as a pale amber oil: ESI/MS m/e 438 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[C:9](Cl)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[C:9]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6]
Reactant: C1CNCCN1
Reactant: O=C(Nc1cc(Cl)cnc1Cl)c1cccc(Cl)c1
Solvent: CC#N
Product: O=C(Nc1cc(Cl)cnc1N1CCNCC1)c1cccc(Cl)c1
Yield: 54.9 %

Procedure:
A solution of 0.500 g (1.66 mmol) of 3-chloro-N-(2,5-dichloro-pyridin-3-yl)-benzamide and 0.71 g (8.3 mmol) of piperazine in acetonitrile (5 mL) are heated to 175° C. for 30 minutes in a microwave reactor. The mixture is concentrated under reduced pressure and the residue is purified by flash silica gel chromatography to provide 0.320 g (54.9%) of 3-chloro-N-(5-chloro-2-piperazin-1-yl-pyridin-3-yl)-benzamide as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C@@H:9]12[C:18](=O)[O:17][C:15](=[O:16])[C@@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14]2.C>C(O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:15](=[O:16])[C@H:10]3[C@H:9]([CH2:14][CH2:13][CH2:12][CH2:11]3)[C:18]2=[O:17])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Solvent: CCO
Product: O=C1[C@H]2CCCC[C@H]2C(=O)N1c1ccc(O)cc1
Temperature: 170 °C
Yield: 69.5 %

Procedure:
A mixture of 4-aminophenol (5.46 g, 50.0 mmol) and cis-1,2-cyclohexanedicarboxylic anhydride (7.71 g, 50.0 mmol) was heated in a round bottom flask at 170° C. for 2 h. After cooling to room temperature the solid material was dissolved in hot ethanol (200 ml), activated charcoal was added and the solution was heated at reflux for 1 h. The solid material was removed by hot filtration. The solvent was partially evaporated. The solids were collected by filtration, washed quickly with a small amount of ethanol and dried in vacuo at 40° C. yielding the title compound (8.52 g, 69% yield, pink solid).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].[Cl:16][CH2:17][CH:18](OS(C)(=O)=O)[CH3:19].O>C1(C)C=CC=CC=1>[Cl:16][CH2:17][CH:18]([N:11]([C:5]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=1[CH3:3])[S:12]([CH3:15])(=[O:14])=[O:13])[CH3:19]
Reactant: Cc1cccc(C)c1NS(C)(=O)=O
Reactant: CC(CCl)OS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1N(C(C)CCl)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
5.2 g of a 80% mineral oil dispersion of sodium hydride are added in small portions, at room temperature, to a suspension of 31.5 g (0.158 moles) of N-(2,6-dimethylphenyl)-methanesulfonamide in 400 ml of dry toluene. The resulting mixture is heated slowly, within about one hour, to 100° C., and then 27.3 g (0.158 moles) of 1-chloro-2-methanesulfonyloxy-propane are added dropwise to the mixture at the same temperature within 0.5 hours. The reaction mixture is stirred at 100°-110° C. for 12 hours, thereafter it is cooled, placed into an ice bath, and 100 ml of water are introduced dropwise. The aqueous phase is separated, the toluene phase is washed with 100 ml of water, twice with 100 ml of 1 n aqueous sodium hydroxide and finally with 100 ml of water, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The thick, yellow, oily residue, weighing 33.9 g, is distilled under reduced pressure. 26.15 g of 1-chloro-2-[N-(2,6-dimethylphenyl)-methanesulfonamido]-propane are obtained as a slightly opalescent oil; b.p.: 150°-154° C./26.6 Pa.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH2:14]([N:16]=[C:17]=[O:18])[CH3:15]>CN(C)C=O.C(OCC)(=O)C>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:17]([NH:16][CH2:14][CH3:15])=[O:18])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: CCN=C=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 44.7 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (150 mg, 0.67 mmol) and ethyl isocyanate (64 μL, 0.81 mmol) in 1 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (50/50, v/v), followed by recrystallization from acetone and hexane, gave the desired product (88 mg, 44%). LC-MS (m/z) 294.0 (M+).
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[CH3:30][O:31][C:32]([CH:34]=[CH:35][C:36]1[N:37]=[CH:38][N:39]2[CH:43]=[CH:42][S:41][C:40]=12)=[O:33].O>C1COCC1>[CH3:30][O:31][C:32]([CH:34]=[CH:35][C:36]1[N:37]=[CH:38][N:39]2[CH:43]=[C:42]([Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])[S:41][C:40]=12)=[O:33]
Reactant: COC(=O)C=Cc1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C=CC(=O)OC)c2s1
Reaction time: 0.25 h

Procedure:
Tri-n-butylstannyl chloride (250 μl) and 2.1 ml of a 1.0 N lithiumbis(trimethylsilyl)amide/THF solution were added in that order to a solution of 7-(2-methoxycarbonylvinyl)imidazo[5,1-b]thiazole (a mixture of geometrical isomers) in dry THF in an argon atmosphere at −78° C. The mixture was stirred at the same temperature for 15 min. Water was added thereto. The mixture was extracted with ethyl acetate, followed by washing with saturated brine. The extract was dried over anhydrous magnesium sulfate and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to give 408 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([F:9])[C:3]=1[F:10].C([Mg]Cl)(C)C.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:3]([F:10])[C:4]=1[F:9]
Reactant: Fc1c(Cl)ccc(Br)c1F
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(Cl)c(F)c2F)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-bromo-4-chloro-2,3-difluorobenzene (720 mg, 3.17 mmol) in tetrahydrofuran (10 mL) was added i-propylmagnesiumchloride (1.90 mL, 3.80 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. Then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (0.98 mL, 4.75 mmol) in tetrahydrofuran (5.0 mL) was added. The reaction mixture was allowed to warm up to room temperature and stirred at RT for 1 h. The mixture was used directly in the next step.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:21]#[N:22])[C:10]([CH3:20])=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:12]=3[F:13])[N:8]=2)[CH2:3][CH2:2]1.[Br:23]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:20][C:10]1[C:9]([C:21]#[N:22])=[C:7]2[N:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[O:5][C:6]2=[C:12]([F:13])[C:11]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1c(CBr)c(-c2ccccc2)c(F)c2oc(C3CC3)nc12
Yield: 81.9 %

Procedure:
Under nitrogen atmosphere, a carbon tetrachloride (12 ml) solution of 2-cyclopropyl-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-173) (1.00 g, 3.42 mmol), N-bromosuccinimide (913 mg, 5.13 mmol) and 2,2′-azobis(isobutyronitrile) (56 mg, 342 μmol) was stirred at 80° C. for 13 hours. After cooling, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=5:1, v/v) to obtain the entitled compound (1.04 g, 82%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: Cc1cccc(CBr)c1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3cccc(C)c3)CC2)cc1
Yield: 96.9 %

Procedure:
The title compound (D27) (63 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (R)-methyl 4-(1-(piperidine-2-carboxamido)cyclopropyl)benzoate (D13) (50 mg, 0.16 mmol) and 3-methyl benzyl bromide (0.033 ml, 0.25 mmol). (Na2CO3: 2.5 eq; reaction time: 6 hrs; 60° C.)