Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]([C:20]2[C:21]([CH:32]=[O:33])=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[O:19])[N:9]=[N:8]1.[CH3:43][Mg]Br>C1COCC1.C(Cl)Cl>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]([C:20]2[C:21]([CH:32]([OH:33])[CH3:43])=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[O:19])[N:9]=[N:8]1
Reactant: C[Mg]Br
Reactant: O=Cc1noc(-c2ccccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(O)c1noc(-c2ccccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
To a solution of 4-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbonyl]-5-(2-chloro-phenyl)-isoxazole-3-carbaldehyde (75 mg, 0.12 mmol) in THF (0.6 mL) at −78° C. under N2, add methylmagnesium bromide (120 μL, 3.0 M in Et2O). Allow the reaction to warm to 0° C. and stir for two h., then quench the reaction with a saturated solution of NH4Cl (1 mL). Dilute the mixture with CH2Cl2 (1 mL), wash with H2O (1 mL) and brine (1 mL). Pass the organic layer through a Varian ChemElute® drying cartridge and concentrate. Purify the residue by chromatography on silica gel using a gradient of 10:1 Hex/EtOAc to 2:1 Hex/EtOAc to afford the title compound (4.3 mg, 6%). MS/ES (M+1)=620.9.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[C:11]([CH3:19])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:34])[CH:32]=[CH2:33])[CH2:27][CH2:26]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C(#N)C>[CH3:19][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]=[C:8]([C:6]1[CH:7]=[C:2]([CH:33]=[CH:32][C:31]([N:28]3[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]3)=[O:34])[CH:3]=[CH:4][C:5]=1[O:20][CH2:21][CH2:22][CH3:23])[NH:17][C:16]2=[O:18]
Reactant: CCCOc1ccc(Br)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Reactant: C=CC(=O)N1CCN(C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ccc(C=CC(=O)N2CCN(C)CC2)cc1-c1nc2c(C)cccc2c(=O)[nH]1

Procedure:
A stirred mixture of 2-(5-bromo-2-n-propoxy-phenyl)-8-methylquinazolin-4(3H)-one (Preparation 11; 0.5 g, 0.0013 mol), 1-methyl-4-propenoylpiperazine (Makromol. Chem., 1984, 185, 1525; 0.24 g, 0.0015 mol), palladium diacetate (0.175 g, 0.00077 mol), tri-o-tolylphosphine (0.30 g, 0.001 mol), triethylamine (1 ml) and acetonitrile (25 ml) was heated under reflux under a nitrogen atmosphere for 4 days. The cool mixture was filtered and the filtrate evaporated to dryness under vacuum. The residue was suspended in saturated aqueous sodium carbonate solution (25 ml), the resulting solution extracted with dichloromethane (50 ml) and the organic extract washed with brine (2×30 ml) dried (Na2SO4) and evaporated under vacuum. Chromatography of the residue on silica gel (10 g), using a methanol in dichloromethane elution gradient (0-4%), gave the title compound which crystallized from hexane-ethyl acetate as a pale pink solid (0.072 g, 12%), m.p. 184-185° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:32])[CH2:9][C:10](=[O:31])[CH:11]=[C:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:30])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH3:29])[CH:20]=3)[CH2:14][CH2:13]2)[CH:5]=[N:6][CH:7]=1.C(O)(=O)C.C(OCC)(=O)C>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:32][C:12]3([CH2:13][CH2:14][N:15]([C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH3:29])[CH:20]=4)[CH2:16][CH2:17]3)[CH2:11][C:10](=[O:31])[CH:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Cc1cc(C(=O)N2CCC(=CC(=O)CC(=O)c3cncc(F)c3)CC2)ccc1OC(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(C(=O)N2CCC3(CC2)CC(=O)C=C(c2cncc(F)c2)O3)ccc1OC(C)C
Temperature: 120 °C
Yield: 91.2 %

Procedure:
A mixture of 1-(5-fluoro-3-pyridyl)-4-[1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidylidene]butane-1,3-dione (100 mg, 0.23 mmol) in acetic acid (1.7 mL, 30 mmol) was heated at 120° C. for 1 h. The reaction mixture was cooled to 25° C. and repartitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine, dried over magnesium sulfate, and concentrated to dryness. The crude product was purified on silica gel utilizing a gradient of 60-100% ethyl acetate in hexanes to yield 10-(5-fluoro-3-pyridyl)-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3-azaspiro[5.5]undec-9-en-8-one (92 mg). 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.61 (d, J=2.7 Hz, 1H), 7.74 (ddd, J=9.0, 2.7, 1.9 Hz, 1H), 7.28-7.24 (m, 2H), 6.84 (d, J=9.0 Hz, 1H), 6.09 (s, 1H), 4.58 (dt, J=12.1, 6.1 Hz, 1H), 3.42 (br s, 2H), 2.68 (s, 2H), 2.27-2.22 (m, 6H), 1.75 (m, 3H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 438.20, found 439.3 (M+1)+; Retention time: 1.78 minutes (3 min run).
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[CH2:32][CH2:33][CH:34]([CH2:36][C:37]([OH:39])=[O:38])[S:35][C:24]1=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)(=O)C>[CH2:16]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[CH2:32][CH2:33][CH:34]([CH2:36][C:37]([O:39][CH:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:38])[S:35][C:24]1=2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)CC1CCc2c(n(Cc3ccccc3)c3ccccc23)S1
Solvent: CCOC(C)=O
Product: O=C(CC1CCc2c(n(Cc3ccccc3)c3ccccc23)S1)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
An excess of diphenyldiazomethane was added to a mixture of 100 mg of 2-(9-benzyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indol-2-yl)acetic acid (prepared as described in Example 83) in 5 ml of ethyl acetate, with stirring, at room temperature, and stirring was continued at this temperature overnight. At the end of this time, the solvent was removed by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a mixture of 6% v/v ethyl acetate in hexane as the eluent, to afford 139 mg of the title compound as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[C:11]([CH2:20][CH:21]=[CH2:22])[C:12]([OH:19])=[C:13]([CH2:16][CH:17]=[CH2:18])[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:23].[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27]>C(#N)C>[CH2:24]([NH:28][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[C:11]([CH2:20][CH:21]=[CH2:22])[C:12]([OH:19])=[C:13]([CH2:16][CH:17]=[CH2:18])[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:23])[CH2:25][CH2:26][CH3:27]
Reactant: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCCCBr
Reactant: CCCCN
Solvent: CC#N
Product: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCCCNCCCC
Temperature: 80 °C
Reaction time: 4 h
Yield: 35 %

Procedure:
1-(4-Bromobutyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone (1.9 g) prepared in Example 43 was dissolved in acetonitrile (50 ml), then n-butylamine (2 ml) was added and stirred at 80° C. for 4 hours. The reaction mixture was extracted with ethyl acetate, and the extract was washed with an aqueous solution saturated with sodium bicarbonate, next with water, then concentrated under reduced pressure. Thus obtained oily residual product was dissolved in ethanol, acidified by adding oxalic acid, then concentrated to dryness, and recrystallized from acetone, there was obtained of 1-(4-n-butylaminobutyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.oxalate in 35% yield.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Na+].[Na+].[OH2:7].Br[CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[C:14]([CH3:25])([CH3:24])[CH2:15][CH2:16][C:17]([CH3:23])([CH3:22])[C:18]=2[C:19]=1CBr>O1CCOCC1>[OH:7][CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[C:14]([CH3:25])([CH3:24])[CH2:15][CH2:16][C:17]([CH3:23])([CH3:22])[C:18]=2[C:19]=1[CH2:1][OH:4]
Reactant: O=C([O-])[O-]
Reactant: O
Reactant: CC1(C)CCC(C)(C)c2c1ccc(CBr)c2CBr
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)CCC(C)(C)c2c1ccc(CO)c2CO

Procedure:
50 g of sodium carbonate was added at room temperature to a mixed solution of 400 ml water and 400 ml dioxane containing 10 g of the unpurified 3,4-dibromomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene, and the mixture was heated under reflux for 11 hours. The dioxane was removed, and then the residue was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then evaporated. The resulting residue was subjected to silica gel column chromatography to give 1.6 g of the title compound as a yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:10]([CH2:11][CH3:12])=[C:9]([CH2:13][C:14]2[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)[C:8]([CH2:26][CH3:27])=[N:7]1)C.[OH-].[Na+]>O1CCCC1.CO.O>[CH2:26]([C:8]1[C:9]([CH2:13][C:14]2[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[C:10]([CH2:11][CH3:12])[N:6]([CH2:5][C:4]([OH:28])=[O:3])[N:7]=1)[CH3:27]
Reactant: CCOC(=O)Cn1nc(CC)c(Cc2cc(C)c(OC)c3c2CCC3)c1CC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCc1nn(CC(=O)O)c(CC)c1Cc1cc(C)c(OC)c2c1CCC2
Reaction time: 1.75 h
Yield: 75.5 %

Procedure:
To a stirred solution of [3,5-Diethyl-4-(7-methoxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-acetic acid ethyl ester of step-III (9.0 gm, 0.0234 mole) in Tetrahydrofuran (40 ml) and Methanol (20 ml), a solution of Sodium hydroxide (1.87 gm, 0.0468 mole) in water (75 ml) was added at 20-30° C. and stirred for 1.5-2 hours. The reaction mixture was poured into water (50 ml) and extracted with Ethyl acetate (2×200 ml). The residual aqueous layer was acidified with dilute Hydrochloric acid. The separated solid was filtered, washed well with water (50 ml) and dried under vacuum at 60-65° C. to yield desired product as off white solid. (6.3 gm).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([Br:14])[C:11]([OH:15])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:23][O:24][C:25](Cl)=[O:26]>O1CCCC1>[C:1]([C:4]1[CH:13]=[C:12]([Br:14])[C:11]([O:15][C:25]([O:24][CH3:23])=[O:26])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)(=[O:3])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CC(=O)c1cc(Br)c(O)c2ncccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Oc1c(Br)cc(C(C)=O)c2cccnc12

Procedure:
26.6 g of 5-acetyl-7-bromo-8-hydroxyquinoline are dissolved in 200 ml of tetrahydrofurane, 11 g of triethylamine are added and 9.5 g of chloroformic acid methyl ester, diluted in 50 ml of tetrahydrofurane, are added dropwise, whilst stirring and cooling. When the exothermic reaction has ended, the triethylamine hydrochloride which has separated out is removed by filtration and the clear filtrate is evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=O)[C:9]=2[S:24][CH3:25])=[CH:4][CH:3]=1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[NH2:48][N:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:48][N:49]3[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]3)=[O:23])[C:9]=2[S:24][CH3:25])=[CH:6][CH:7]=1
Reactant: NN1CCCCC1
Reactant: CSc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CSc1c(C(=O)NN2CCCCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 16 h

Procedure:
To a magnetically stirred solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylic acid (4.69 g, 11.3 mmol) in dichloromethane (100 ml) was successively added 7-aza-1-hydroxybenzotriazole (HOAt) (2.2 g, 16.0 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (3.1 g, 16.1 mmol) and 1-aminopiperidine (1.6 gram, 16.0 mmol). After stirring for 16 h, the resulting mixture was successively washed with water (3×), dried over Na2SO4, filtered and concentrated to give a crude solid. This crude solid was further purified by flash chromatography (silica gel, EtOAc/heptane=22/78 (v/v)) and trituration with n-heptane/methanol to give 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide: compound 1 (0.55 gram, 10% yield). Melting point: 172.4-174.5° C. 1H-NMR (CDCl3, 400 MHz) δ 1.41-1.49 (m, 2H), 1.72-1.81 (m, 4H), 2.40 (s, 3H), 2.83-2.95 (m, 4H), 7.15 (br d, J=8 Hz, 2H), 7.28-7.35 (m, 4H), 7.42 (br d, J=2 Hz, 1H), 7.94 (br s, 1H). 13C-NMR (CDCl3, 100 MHz) δ 20.03, 23.32, 25.29, 57.02, 113.66, 126.20, 127.99, 128.74, 130.36, 130.48, 131.24, 132.85, 135.59, 135.64, 136.41, 147.08, 147.30, 158.62.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9](O)=[O:10])=[CH:3][CH:2]=1.Cl.[CH3:27][O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32].CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([C:9]([NH:32][CH2:31][CH2:30][C:29]([O:28][CH3:27])=[O:33])=[O:10])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNC(=O)[C@@H](CC(=O)OC(C)(C)C)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 92.4 %

Procedure:
A solution of (R)-2-(biphenyl-4-ylmethyl)-4-tert-butoxy-4-oxobutanoic acid (142 mg, 0.417 mmol), 3-amino-propionic acid methyl ester hydrochloride (76 mg, 0.542 mmol), WSC hydrochloride (120 mg, 0.626 mmol), 1-hydroxy-7-azabenzotriazole (85 mg, 0.626 mmol) and DIPEA (0.219 ml, 1.251 mmol) in DMF (4 mL) is allowed to stir at room temperature under nitrogen for 13 hours. The reaction is quenched with H2O. The products are extracted with ethyl acetate, washed with aqueous 1M HCl and then with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on 12 g of silica gel (heptane/EtOAc=70:30 to 0:100) to give (R)-tert-butyl 3-(biphenyl-4-ylmethyl)-4-(3-methoxy-3-oxopropylamino)-4-oxobutanoate (164 mg, 91%). HPLC retention time=1.59 minutes (condition A); MS (ES+)=425.4 (m); 369.4 (m-tBu+1; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.24-2.44 (m, 2 H) 2.67-2.79 (m, 3 H) 2.89-2.96 (m, 1 μl) 3.28-3.36 (m, 1 H) 3.45-3.53 (m, 1 H) 7.23 (d, J=5.8 Hz, 2 H) 7.33 (t, J=7.35 Hz, 1 H) 7.41-7.44 (m, 2 H) 7.51 (d, J=8.1 Hz, 2 H) 7.58 (d, J=7.4 Hz, 2 H).
Reaction SMILES: [N:1]1[CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=3[S:7][C:6]=12.C(O)(=O)C.[O-:19][C:20]#[N:21].[K+].[OH-].[NH4+]>O>[N:1]1[CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[C:11]([NH:14][C:20]([NH2:21])=[O:19])[CH:12]=[CH:13][C:8]=3[S:7][C:6]=12
Reactant: Nc1ccc2c(c1)N1CCCN=C1S2
Reactant: N#C[O-]
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccc2c(c1)N1CCCN=C1S2
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3 parts of 3,4-dihydro-2-H-pyrimido[2,1-b]benzothiazol-7-amine in 16 parts of acetic acid are added 32 parts of water. Then there is added dropwise a solution of 1.46 parts of potassium cyanate in 32 parts of water (slightly exothermic reaction). Upon completion, stirring is continued overnight at room temperature. The reaction mixture is alkalized with ammonium hydroxide and the whole is stirred while cooling at 10° C. The precipitated product is filtered off and crystallized twice: first from 2-methoxyethanol and then from 1-butanol, yielding 0.6 parts of N-(3,4-dihydro-2H-pyrimido[2,1-b]benzothiazol-7-yl)urea; mp. 245.9° C.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.Br[CH2:36][C:37]([OH:39])=[O:38]>C1COCC1.O>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:8][CH2:9][CH2:10][O:11][CH2:36][C:37]([OH:39])=[O:38])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CBr
Reactant: OCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 59 %

Procedure:
2-(Triphenylmethoxy)ethanol (3.98 g, 0.013 mol) was dissolved in dry THF (50 ml) and a 2.5 M solution of butyllithium in hexane (5.5 ml, 0.0137 mol) was added at 0° C. A solution of bromoacetic acid (1.81 g, 13.0 mmol) was separately treated with a 2.5 M solution of butyllithium in hexane (5.5 ml, 13.7 mmol) at 0° C. before the two solutions were mixed. This reaction mixture was heated at reflux for 68 h, cooled, and water (200 ml) was added. Washing with ethyl acetate was followed by acidification of the aqueous phase with 0.5 M citric acid solution (50 ml). Extraction with ethyl acetate (2 × 100 ml) and drying (MgSO4) provided crude [2-(triphenylmethoxy)ethoxy]acetic acid (2.78 g, 58%). This acid was dissolved in dichloromethane (30 ml) and dicyclohexylcarbodiimide (1.72 g, 0.0083 mol) was added, followed by 4-pyrrolidinopyridine (0.11 g, 0.00074 mol) and ethanol (0.89 ml, 2 equiv.) (A. Hassner et al., Tetrahedron Lett. (1978) 4475). The reaction mixture was stirred for 16 h at room temperature and filtered to remove dicyclohexyl urea. The filtrate was evaporated, and the residue was purified by flash chromatography on silica gel (3 × 20 cm). Elution with cyclohexane containing 1-3% ethyl acetate provided the desired [2-(triphenylmethoxy)ethoxy]acetic acid ethyl ester (1.5 g, 50%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:20][CH:21]=2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(CCN(C)C)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(CCN(C)C)cc1
Yield: 39.9 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{4-[2-(dimethylamino)ethyl]phenylamino}-1,5-naphthyridin-3-yl)ethanone (40 mg, 0.11 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.15 mmol) followed by formation of the dihydrochloride salt to afford the desired product (17 mg, 28%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.30 (s, 1H), 8.43 (d, J=9.0 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 7.52 (br s, 2H), 7.42 (d, J=8.5 Hz, 2H), 7.37 (d, J=8.5 Hz, 2H), 3.40-3.32 (m, 2H), 3.22-3.13 (m, 2H), 2.96 (s, 6H), 2.79 (s, 3H); ESI MS m/z 495 [M+H]+; HPLC>99% (AUC), tR=9.91 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH:8]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:5]=[C:4]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[N:3]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccccc1)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
To a cooled (−15° C.) solution of methyl 2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)acetate (0.100 g; 0.295 mmol) in dry DMF (1.5 mL) was wadded a 1N solution of LHMDS in THF (0.324 mL; 0.324 mmol) dropwise and the mixture was stirred at (−15° C.) for 15 min, followed by the dropwise addition of benzyl bromide (0.070 mL; 0.589 mmol). After stirring for 2 h at (−15° C.) the mixture was allowed to warm up to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride and the mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.087 g (60%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@H:4]([C@@H:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:15][CH2:16][OH:17])[N:5]=[C:6]([O:12][CH3:13])[C@@H:7]([CH:9]([CH3:11])[CH3:10])[N:8]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(C(C)C)CC)(C)C>ClCCl.CCOCC>[CH3:1][O:2][C:3]1[C@H:4]([C@@H:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:15][CH2:16][O:17][S:27]([CH3:26])(=[O:29])=[O:28])[N:5]=[C:6]([O:12][CH3:13])[C@@H:7]([CH:9]([CH3:10])[CH3:11])[N:8]=1
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1[C@H](CCO)c1ccc(OC)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1[C@H](CCOS(C)(=O)=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The above oil 3(R)-[(2S,5R)-2,5-dihydro-3,6-dimethoxy-5-(1-methylethyl)-2-pyrazinyl]-3-(4-methoxyphenyl)propanol (28) (17.7 g) was dissolved in 300 mL of dichloromethane. To the solution at −5° C. was added methane sulfonyl chloride (8.02 g, 5.42 mL, 70 mmol) followed by diisopropylethylamine (DIPEA, 12 mL, 70 mmol) dropwise over 10 min. The reaction was stirred at 0° C. for 2 hour. The light yellow solution was diluted with 2 L of ether and was washed with water (3×200 mL) and brine (2×200 mL). After it was dried over sodium sulfate, the solution was concentrated to a volume of 160 mL under vacuum at 20° C. TLC in EA/H (=1:1): Rf=0.74, as a major spot; Rf=0.21, as a minor spot.