Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[CH3:38][C:39]1[CH:44]=[CH:43][C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][C:40]=1[N+:54]([O-:56])=[O:55].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:38][C:39]1[CH:44]=[CH:43][C:42]([C:2]2[N:3]=[C:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7]4[N:15]=[CH:16][CH:17]=[CH:18][C:6]=4[N:5]3[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([C:26]3([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:27][CH2:28][CH2:29]3)=[CH:22][CH:21]=2)=[CH:41][C:40]=1[N+:54]([O-:56])=[O:55]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Cl)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1[N+](=O)[O-]
Temperature: 160 °C
Yield: 95.7 %

Procedure:
A mixture of tert-butyl {1-[4-(2-chloro-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50.0 mg, 0.0835 mmol), 4-methyl-3-nitrophenylboronic acid pinacol ester (33.6 mg, 0.125 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5.91 mg, 0.00835 mmol) and 2M Na2CO3 aq. (0.0835 mL, 0.170 mmol) in DMF (1.00 mL) was heated at 160° C. under microwave irradiation for 1 hour. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water(×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=1:4→1:3→1:2) to afford desired product (49.1 mg, 95.7%) as pale yellow solid. 1HNMR (CDCl3) 400 MHz δ: 8.21 (s, 1H), 8.16 (dd, J=7.8, 1.4 Hz, 1H), 8.02 (dd, J=4.6, 1.4 Hz, 1H), 7.67 (dd, J=8.2, 1.8 Hz, 1H), 7.42 (d, J=8.2 Hz, 2H), 7.31 (td, J=7.6, 1.5 Hz, 1H), 7.22-7.11 (m, 4H), 7.00-6.93 (m, 1H), 6.85 (d, J=7.8 Hz, 1H), 6.61 (dd, J=7.8, 5.0 Hz, 1H), 6.50 (s, 1H), 5.24 (br s, 1H), 2.67-2.27 (m, 4H), 2.56 (s, 3H), 2.23-2.07 (m, 1H), 1.97-1.85 (m, 1H), 1.39 (br s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([OH:6])([OH:5])[CH3:4].C(O)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=CC=1>>[CH3:1][O:2][C:3]1([CH3:4])[O:6][CH:12]2[CH:11]([CH2:8][CH2:13]2)[O:5]1
Reactant: O=C(O)c1ccccc1
Reactant: COC(C)(O)O
Product: COC1(C)OC2CCC2O1
Yield: 965.7 %

Procedure:
88.0 g (1.0 mol) of cyclobutane-cis-1,2-diol, 120.0 g (1.0 mol) of orthoacetic acid methyl ester and 10.0 g of benzoic acid are heated from 80° to 120° C. in the course of 3 hours. Methanol which forms is distilled off continuously. Fractional distillation gives 114.0 g (79%) of 3-methoxy-3-methyl-2,4-dioxa-bicyclo[3,2,0]heptane (stereoisomer mixture) of boiling point12 52°-53°.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH2:15]>>[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH:15][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])=[O:9]
Reactant: NCc1cccc(F)c1
Reactant: Cc1ccsc1C(=O)O
Product: Cc1ccsc1C(=O)NCc1cccc(F)c1
Yield: 96 %

Procedure:
Following the procedure as described in Preparation 18, making variations only as required to use 3-methylthiophene-2-carboxylic acid in place of 3-methylfuran-2-carboxylic acid to react with 3-fluorobenzylamine in place of benzylamine, N-(3-fluorobenzyl)-3-methylthiophene-2-carboxamide was obtained as a colorless solid in 96% yield: 1H NMR (300 MHz, CDCl3) δ 7.35-7.25 (m, 2H), 7.15-6.94 (m, 3H), 6.90 (d, J=5.0 Hz, 1H), 6.14 (br s, 1H), 4.61 (d, J=5.9 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 250.2 (M+1).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][C:14]([CH2:16][C:17]3(O)C4C[CH:20]5[CH2:21][CH:22](C[CH:18]3[CH2:19]5)[CH2:23]4)=[N:13][C:12]=2[CH:28]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH2:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:17]1=[CH:16][C:14]1[S:15][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:28][C:12]=2[N:13]=1
Reactant: COc1ccc2sc(CC3(O)C4CC5CC(C4)CC3C5)nc2c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc2sc(C=C3CCCCCC3)nc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
187 μl of methanesulfonyl chloride are added to a mixture of 350 mg of 2-(5-methoxybenzothiazol-2-ylmethyl)cycloheptan-2-ol (formula IX), 665 μl of triethylamine and a catalytical amount of 4-N,N-dimethylaminopyridine in 12 ml of dry dichloromethane at about 0°. The mixture is stirred for about 12 hours at room temperature, 187 μl of methansulfonyl chloride and 665 μl of triethylamine are added and the resultant reaction mixture is stirred at about 40° for about 48 hours. The mixture is diluted with 100 ml of ethyl acetate and then extracted with 1 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine. The organic phase is dried and the solvent is evaporated off. The residue is subjected to chromatography. The title compound is obtained [13C-NMR (125.8 MHz): 166.528, 158.978, 155.645, 154.597, 126.878, 121.337, 119.750, 114.743, 105.127, 55.561, 39.394, 33.143, 29.921, 29.344, 28.775, 26.435],
Reaction SMILES: CC(C)([O-])C.[Na+].O1CCOCC1.[CH3:13][N:14]([CH3:38])[C:15]([N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2([CH2:31][CH2:30][N:29]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)[CH2:19][CH2:18]1)=[O:16].Cl[C:40]1[N:41]=[C:42]([CH3:47])[C:43]([CH3:46])=[N:44][CH:45]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)(Cl)Cl.CC#N>[CH3:47][C:42]1[N:41]=[CH:40][C:45]([N:35]2[CH2:36][CH2:37][CH:32]([N:29]3[CH2:28][CH2:27][C:20]4([C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:17]([C:15]([N:14]([CH3:38])[CH3:13])=[O:16])[CH2:18][CH2:19]4)[CH2:31][CH2:30]3)[CH2:33][CH2:34]2)=[N:44][C:43]=1[CH3:46]
Reactant: Cc1ncc(Cl)nc1C
Reactant: CN(C)C(=O)N1CCC2(CCN(C3CCNCC3)CC2)c2ccccc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Cc1ncc(N2CCC(N3CCC4(CCN(C(=O)N(C)C)c5ccccc54)CC3)CC2)nc1C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Pd2(dba)3-CHCl3 (5 mg, 0.5 mol %), ligand 1 (8 mg, 2 mol %) and 1.4 eq sodium tert-butoxide (13 mg, 0.14 mmol) were weighed in air and transferred into a microwave tube, followed by dioxane (750 μL), 1.0 eq N,N-dimethyl-1-(piperidin-4-yl)-2′H-spiro[piperidine-4,4′-quinoline]-1′(3′H)-carboxamide (36 mg, 0.10 mmol) and 1.0 eq 5-chloro-2,3-dimethylpyrazine (14 mg). The tube was flushed with nitrogen, capped and stirred at 80° C. for 3 hours. The reaction was cooled to room temperature, diluted with methanol (500 μL), filtered (Whatman 0.45 μm PTFE) and subjected to reverse-phase HPLC purification (2-40% CH3CN gradient [w/0.1% TFA (aq)] over t=10 minutes, 750 μL injected, 35 mL/min) to yield compound no. 20. LC/MS (10-99% CH3CN/0.05% TFA gradient over 5 min): m/z 463.4, retention time 2.13 minutes.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[CH3:20][N:21]1[C:25]([C:26](O)=[O:27])=[CH:24][N:23]=[CH:22]1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:26]([C:25]4[N:21]([CH3:20])[CH:22]=[N:23][CH:24]=4)=[O:27])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: Cn1cncc1C(=O)O
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3cncn3C)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and 3-methyl-3H-imidazole-4-carboxylic acid, the title compound was prepared. MS: m/e=389(M+H+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Br:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20](O)=[CH:19][C:18]=1[CH3:25].C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:20]1[CH:21]=[C:22]([CH3:23])[C:17]([Br:16])=[C:18]([CH3:25])[CH:19]=1)(=[O:5])=[O:4]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoromethanesulfonic anhydride (2.0 mL) was added dropwise to a solution of 4-bromo-3,5-dimethylphenol (CAS No. 7463-51-6) (2.0 g) and TEA (1.94 mL) in DCM (20 mL) under ice-cooling over three minutes. The reaction mixture was stirred at room temperature for 30 minutes. Ice and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was sequentially washed with 1 N hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 5%) to give the title compound (3.20 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:10][N:11](C=O)C>>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:10]#[N:11])=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)cnc1N
Product: Cc1cc(C#N)cnc1N
Temperature: 150 °C
Yield: 70 %

Procedure:
A mixture of 2-Amino-5-bromo-3-methylpyridine (15.49 g, 82.8 mmol) and Cu(I)CN (9.27 g, 103.5 mmol) in DMF (160 mL) was heated at 150° C. for 24 h. The reaction mixture was poured onto water and the solid which formed was extracted by using ethylacetate (600 mL, 3 times) from aq. NH4OH. The solvent was evaporated and the precipitate purified by chromatography (SiO2, hexanes/EtOAc 4:6). Yield 70%, mp 198-200° C., (Lit. mp 203-205° C.; see Dunn A. D. and Norrie R. J. Prakt. Chem./Chem.-Ztg, 338 (7), 663-666 (1996). Lit. melting point not reported via palladium-catalyzed cyanation; see Maligres, P. et al., Tetrahedron Lett., 40, 8193-8195 (1999).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[C:30](=[S:33])([O-:32])[CH3:31].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:30](=[O:32])([S:33][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C@H:9]([NH:22][C:23]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29])[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])=[O:11])[CH:3]=1)[CH3:31]
Reactant: CC([O-])=S
Reactant: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(Br)c2)NC(=O)OC(C)(C)C)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(SC(C)=O)c2)NC(=O)OC(C)(C)C)cc1
Yield: 65 %

Procedure:
A solution of (5)-tert-butyl 3-(3-bromophenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-ylcarbamate (464 mg, 1.0 mmol), potassium ethanethioate (171.3 mg, 1.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol), xantphos (58 mg, 0.1 mmol) and DIPEA (0.35 ml, 2 mmol) in 1,4-dioxane (4 ml) was heated at 150° C. for 20 minutes in a microwave reactor. The mixture was filtered through celite and the celite was washed with EtOAc (2×50 ml). The organic layer was dried with Na2SO4, filtered and concentrated. The crude product was introduced to a silica gel loading column and purified by column chromatography (20-45% EtOAc/hexanes) to provide the desired product (300 mg, 0.65 mmol), 65%. MS (m/z) 459 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([S:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[OH:24])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:6])[CH3:5].[Na+].Cl[CH2:27][C:28]([O-:30])=[O:29].Cl>O1CCCC1.O>[CH3:16][C:13]([C:11]1[CH:10]=[C:9]([S:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[O:24][CH2:27][C:28]([OH:30])=[O:29])[CH:8]=[C:7]([C:4]([CH3:3])([CH3:5])[CH3:6])[CH:12]=1)([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2O)cc(C(C)(C)C)c1
Reactant: O=C([O-])CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2OCC(=O)O)cc(C(C)(C)C)c1
Reaction time: 1.5 h

Procedure:
Sodium hydride (0.33 g, 0.0138 mole) was added to a solution of trans-2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexanol (3.4 g, 0.0106 mole) in tetrahydrofuran (50 ml) at 0° C. After stirring the reaction mixture for 1.5 hours, the tetrahydrofuran was removed by rotary evaporation. Dimethyl sulfoxide (75 ml) was added followed by chloroacetic acid sodium salt (1.48 g, 0.0127 mole), and the reaction mixture was stirred at room temperature for 10 days. Water (100 ml) was added dropwise to the mixture followed by 10% hydrochloric acid (10 ml). The product was extracted twice with 200 ml of ethyl acetate. The combined ethyl acetate extracts were washed twice with 200 ml of water, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was purified by chromatography on silica gel. The structure was supported by NMR and elemental analysis (378.6+1/4 mole H2O).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[N:13]=[CH:14][CH:15]=[CH:16][C:7]1=2)=[O:5].O.O.[Cl-]>CO>[NH2:21][C:19]1[CH:18]=[CH:17][C:3]([C:4]([N:6]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]3[N:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)=[O:5])=[C:2]([Cl:1])[CH:20]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCCCc2ncccc21
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: Nc1ccc(C(=O)N2CCCCc3ncccc32)c(Cl)c1
Yield: 85.7 %

Procedure:
A mixture of 3.31 g of 6,7,8,9-tetrahydro-5-(2-chloro-4-nitrobenzoyl)-5H-pyrido[3,2-b]azepine and 6.78 g of stannus chloride dihydrate (SnCl2.2H2O) in 200 ml of methanol is refluxed for 2 hours under argon. The solvent is removed under vacuum and 5 ml of saturated NaHCO3 solution and solid NaHCO3 added to bring the pH to 7. The mixture is extracted with ethyl acetate, the extract filtered through diatomaceous earth and the filtrate washed with saturated NaHCO3, H2O, brine and dried (Na2SO4). The filtrate is passed through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness to give 2.58 g of an amorphous solid. Anal. Calc'd for C16H16ClN3O; C,59.9; H,5.7; N,13.1; C1, 11.1 Found: C,60.5; H,5.0; N,12.9; Cl,11.6.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10](N=C(C)C)[CH2:9][CH:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:7][C:6]=2[CH:21]=1.[CH3:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=O.OS(O)(=O)=O>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5]3=[C:6]([O:7][CH:8]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:9][N:10]3[C:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][C:25]2=3)[CH:21]=1
Reactant: CC(C)=NN1CC(c2ccccc2)Oc2cc(C)ccc21
Reactant: CN1CCCCC1=O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1cc2c3c(c1)c1c(n3CC(c3ccccc3)O2)CCN(C)C1
Temperature: 95 °C
Yield: 5.4 %

Procedure:
7-Methyl-2-phenyl-N-(propan-2-ylidene)-2H-benzo[b][1,4]oxazin-4(3H)-amine (1.3 g) and N-methyl piperidone (0.629 g) were dissolved in dioxane (2 mL). To this mixture was added 7% H2SO4 in Dioxane (25 mL) and the resulting reaction mixture was heated at 95° C. for 2 h. Reaction was monitored by TLC. After completion of reaction, the mixture was concentrated under reduced pressure, and the residue basified with NaOH solution to pH 12. The mixture was extracted with EtOAc (3×100 mL), and the organic layer dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography using silica (100-200 mesh size) using 3% MeOH/DCM as eluent. The purified compound was further purified using preparative TLC using 5% MeOH/DCM as mobile phase to obtain pure product as a light brown solid (0.08 g). 1H NMR (CD3OD, HCl Salt): d (ppm): 7.56 (d, 2H), 7.42 (m, 3H), 6.90 (s, 1H), 6.56 (s, 1H), 5.32 (m, 1H), 4.70 (m, 1H), 4.50 (m, 1H), 4.38 (m, 1H), 4.05 (m, 1H), 3.82 (m, 1H), 3.58 (m, 1H), 3.20 (m, 2H), 3.10 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:7]1
Reactant: O=C=NCCc1ccccc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(NCCc1ccccc1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1

Procedure:
Example 8 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and (2-isocyanatoethyl)benzene (18.9 μl) to give the title compound (0.0312 g). LC-MS (System A): Rt 2.29 mins, Mass Spectrum m/z 422 [MH+].
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23](=[O:32])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[Cl:31])[CH:17]=2)[CH2:11][C@@H:10]1[CH3:33])=O)(C)(C)C>O1CCOCC1>[Cl:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C@H:12]2[CH2:13][CH2:14][NH:9][C@@H:10]([CH3:33])[CH2:11]2)[CH:17]=1)=[O:32]
Reactant: C[C@H]1C[C@@H](Oc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1C[C@@H](Oc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1
Temperature: 100 °C

Procedure:
Add 0.7 mL of conc. hydrochloric acid into a solution of 4-[3-(2-chloro-4-fluoro-benzoylamino)-phenoxy]-cis-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 2 (Preparation 86, 0.464 g) in 1,4-dioxane 20 mL and heat at 100° C. for 40 min. Partition between ethyl acetate and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel column (10 g, solvent: dichloromethane-2M NH3 in methanol, gradient) to give the title compound (0.298 g). Mass spectrum (electrospray) m/z=363 (M+1); 1H NMR (CDCl3): 7.94 (br s, 1H), 7.77 (dd, 1H), 7.41 (t, 1H), 7.24 (t, 1H), 7.19 (dd, 1H), 7.08 (m, 2H), 6.72 (m, 1H), 4.29 (m, 1H), 3.46 (s, 3H), 3.17 (m, 1H), 2.73 (m, 2H), 2.14 (m, 2H), 1.69 (br, 1H), 1.51 (m, 1H), 1.22 (m, 1H), 1.14 (d, J=6.4 Hz, 3H).
Reaction SMILES: [N:1]([CH:4]([O:6][CH2:7][CH2:8][OH:9])[CH3:5])=[N+:2]=[N-:3].[H-].[Na+].[CH2:12]([O:14][C:15](=[O:18])[CH2:16]Br)[CH3:13]>O1CCCC1>[CH2:12]([O:14][C:15](=[O:18])[CH2:16][O:9][CH2:8][CH2:7][O:6][CH:4]([N:1]=[N+:2]=[N-:3])[CH3:5])[CH3:13]
Reactant: CC(N=[N+]=[N-])OCCO
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COCCOC(C)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(1-azido-ethoxy)-ethanol (0.15 g, 1.14 mmol) in dry tetrahydrofuran (THF) (5 ml) was added NaH (60% dispersion, 0.08 g, 2 mmol) at 0° C. After 15 minutes, ethyl-2-bromoacetate (0.222 ml, 2 mmol) was added. The reaction was maintained at this temperature for 15 minutes and then warmed up to room temperature. The reaction was quenched by addition of saturated aqueous NaHCO3 (5 ml) after 1 hr. After a further period of 5 min, the mixture was partitioned between DCM (50 ml) and saturated aqueous NaHCO3 (50 ml). The aqueous layer was further extracted with DCM (50 ml). All the DCM extracts were combined, dried over MgSO4 and evaporated under reduced pressure. The title compound was obtained as an oil (0.162 g, 65.5%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:31]1([NH2:34])[CH2:33][CH2:32]1>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:34][CH:31]4[CH2:33][CH2:32]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: CCO
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)NC4CC4)c3)C(C)(C)C2=O)cc1
Temperature: 50 °C

Procedure:
This compound may be prepared as obtained in stage c) of Example 9, but starting with 200 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9, 4 mL of ethanol and 32.3 mg of cyclopropanamine. After heating for one hour at a temperature of 50° C., and chromatography on a column of silica, eluting with a mixture of heptane/ethyl acetate (gradient from 100/0 to 0/100 by volume), 76.1 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-3-cyclopropylurea are obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=1[CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(OCc2ccccc2OCc2ccccc2)cc1
Yield: 140.9 %

Procedure:
Methyl 4-(2-(benzyloxy)benzyloxy)benzoate (1.01 g, 1.91 mmol) was dissolved in THF (20 ml) and methanol (7 ml). The solution was treated with NaOH (1N, 6 ml). The reaction was heated at reflux for 3 hours and then concentrated at reduced pressure. The pH was adjusted to pH1 with concentrated HCl and the solid filtered, washed with water and dried to give the title compound as a white solid (0.9 g, 98%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.[NH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:21]1([C:9]([C:8]2[C:7]([O:6][C:5]3[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:1])([F:20])[F:19])[CH:4]=3)=[N:15][CH:14]=[CH:13][CH:12]=2)=[O:11])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C(O)c1cccnc1Oc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccnc1Oc1cccc(C(F)(F)F)c1)N1CCCc2ccccc21
Temperature: 100 °C
Yield: 55.5 %

Procedure:
To a solution of 2-(3-trifluoromethyl-phenoxy)-nicotinic acid (200 mg, 0.71 mmol, 1.0 equiv) in anhydrous DMF (3 mL) was added 1,2,3,4-tetrahydro-quinoline (113 mg, 107 μL, 0.85 mmol, 1.2 equiv; [CAS RN 635-46-1]), N-ethyldiisopropylamine (457 mg, 617 μL, 3.53 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and HATU (322 mg, 0.85 mmol, 1.2 equiv; [CAS RN 148893-10-1]). The reaction mixture was heated by microwave irradiation to 100° C. for 5 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 157 mg (56%) of the title compound. MS (ISP): 399.2 [M+H]+.