Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:13][C:3]=1[O:4][CH:5]([C:10](=O)[CH3:11])[C:6](OC)=[O:7].C(OC)(=O)[NH:32][NH2:33].Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:27])([F:26])[F:28])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:13][C:3]=1[O:4][C:5]1[C:6]([OH:7])=[N:32][NH:33][C:10]=1[CH3:11]
Reactant: COC(=O)C(Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(C)=O
Reactant: COC(=O)NN
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1[nH]nc(O)c1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 99.1 %

Procedure:
3.09 g of methyl 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-oxobutyrate and 1.23 g of methyl carbazate were suspended in 30 ml of toluene, and the mixture was heated under reflux for 5 hours. The solution was cooled to room temperature, then, the reaction solution was poured into ice water and dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was washed with a mixed solvent of n-hexane:ethyl acetate (3:1) to obtain 2.94 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxy-5-methylpyrazole.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([C:33]([F:36])([F:35])[F:34])=[N:10][C:11]2[C:16]([C:17]=1Cl)=[CH:15][C:14]([C:19]([C:27]1[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[OH:20])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38].C[O-].[Na+].CO>>[CH2:1]([C:8]1[C:9]([C:33]([F:36])([F:35])[F:34])=[N:10][C:11]2[C:16]([C:17]=1[O:38][CH3:37])=[CH:15][C:14]([C:19]([C:27]1[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[OH:20])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]
Reactant: Cn1cncc1C(O)(c1ccc2nc(C(F)(F)F)c(Cc3ccccc3)c(Cl)c2c1)c1ccccn1
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1c(Cc2ccccc2)c(C(F)(F)F)nc2ccc(C(O)(c3ccccn3)c3cncn3C)cc12
Temperature: 82 °C

Procedure:
A mixture of (3-benzyl-4-chloro-2-(trifluoromethyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol•TFA (84 mg, 0.11 mmol, Example 97) and 0.5 M NaOMe in MeOH (0.80 mL, 0.40 mmol) in a sealed tube was heated at 82° C. for 24 hours. The solvent was evaporated, and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.96 (s, 1H), 8.61 (d, J=4.04 Hz, 1H), 8.28 (d, J=2.02 Hz, 1H), 8.20 (d, J=9.09 Hz, 1H), 8.00 (dd, J=2.02, 9.09 Hz, 1H), 7.96 (dd, J=2.02, 8.08 Hz, 1H), 7.80 (d, J=8.08 Hz, 1H), 7.39-7.45 (m, 1H), 7.19-7.26 (m, 2H), 7.12-7.18 (m, 1H), 7.09 (d, J=2.02 Hz, 1H), 7.06 (d, J=7.07 Hz, 2H), 4.36 (s, 2H), 3.78 (s, 3H), 3.63 (s, 3H); MS m/e 505.0 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[N:11]1([CH2:14][CH2:15][C:16]2([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: O=C1CCCN1CC1(CCN2CCN(Cc3ccccc3)CC2)CCCC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1CCCN1CC1(CCN2CCNCC2)CCCC1
Reaction time: 7 h

Procedure:
A mixture of 1-[[1-[2-(4-benzyl-1-piperazinyl)ethyl]cyclopentyl]methyl]-2-pyrrolidinone (408 mg) and palladium hydroxide (41 mg) in methanol (5.5 ml) was stirred under hydrogen (4 kg) for 7 hours. After hydrogen was replaced with nitrogen, the mixture was filtered through Celite. The filtrate was concentrated in vacuo to provide a yellow oil. (345 mg/100%)
Reaction SMILES: [CH2:1]([C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CN1C=CN=C1.[N+:29]([C:32]1[CH:37]=[C:36]([N+:38]([O-])=O)[CH:35]=[CH:34][C:33]=1Cl)([O-])=O>C(C(C)=O)C>[CH2:1]([C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][C:35]1[CH:34]=[CH:33][C:32]([NH2:29])=[CH:37][C:36]=1[NH2:38])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCCCCCCCCCCCCCCc1cccc(O)c1
Agent: Cn1ccnc1
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCc1cccc(Oc2ccc(N)cc2N)c1
Reaction time: 1.5 h

Procedure:
4-(-3-Pentadecylphenoxy)benzene-1,3-diamine is prepared as described in chapter 2 of Jinu Suju Mathew, “Novel Thermally Stable Polymers from a Renewable Resource (Cashew Nut Shell Liquid): Thesis, Characterization, and Applications,” Ph.D. Thesis, U. of Pune, July 2001, the disclosure of which is totally incorporated herein by reference. More specifically, to a 100 mL three necked round bottom flask equipped with a reflux condenser, thermowell, and magnetic stirrer is added 5 g (0.016 mol) of 3-pentadecylphenol, 1.35 g (1.3 mL, 0.016 mol) of N-methyl imidazole, and 50 mL methyl ethyl ketone, and the solution is stirred for 1.5 hours. Thereafter 3.33 g (0.016 mol) of 2,4-dinitrochlorobenzene is added to this mixture and the reaction mixture is refluxed for 3 hours. The solvent is then distilled off and the residue dissolved in ether. The ether solution is then washed with water, 5% NaOH solution, and again with water. The ether solution is then dried with sodium sulfate and the ether distilled off to obtain the crude product. The crude product is then recrystallized from petroleum ether at 40 to 60° C. to obtain pure 1-(3-pentadecylphenoxy)-2,4-dinitrobenzene, of the formula
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].O=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.N1CCCC1>O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Solvent: C1CCNC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
A solution of 5-nitro-1H-indole (1 g, 6.17 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (2.458 g, 12.33 mmol) and pyrrolidine (1.530 mL, 18.50 mmol) were refluxed for 48 hours. The reaction was brought to room temperature, diluted with water (50 mL) and product was extracted into ethyl acetate (2×50 mL). The combined ethyl acetate layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was diluted with isopropanol: hexanes, 1:6 (20 mL). After stirring for 15 minutes, the solid was filtered off, washed with hexanes (2×10 mL), and dried to obtain tert-butyl 4-(5-nitro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.515 g, 71.5%). 1H NMR (CDCl3) δ 8.83 (d, 1H, J=1.5 Hz), 8.60 (brs, 1H), 8.14 (dd, 1H, J=2.1, 9.0 Hz), 7.42 (d, 1H, J=9.0 Hz), 7.31 (d, 1H, J=2.1 Hz), 6.21 (s, 1H), 4.20-4.16 (m, 2H), 3.70 (t, 2H, J=5.7 Hz), 2.60-2.50 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][N+:3]=1[O-:12].[NH2:13][C@@H:14]([CH2:17][CH3:18])[CH2:15][OH:16]>C(O)C>[OH:16][CH2:15][C@@H:14]([NH:13][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][N+:3]=1[O-:12])[CH2:17][CH3:18]
Reactant: CC[C@H](N)CO
Reactant: Cc1c[n+]([O-])c(Cl)cc1[N+](=O)[O-]
Solvent: CCO
Product: CC[C@@H](CO)Nc1cc([N+](=O)[O-])c(C)c[n+]1[O-]
Yield: 57.5 %

Procedure:
2-Chloro-5-methyl-4-nitropyridine N-oxide (200 mg, 1.06 mmol, 1.0 equivalent) was dissolved in ethanol (1.5 mL). (S)-2-Aminobutanol (284 mg, 3.2 mmol, 3.0 equivalent) was then added and the resulting mixture was refluxed for 16 hours. The crude solution was then purified by reversed phase HPLC (acetonitrile/water/TFA) to afford the title compound as a brown solid (146 mg, 0.61 mmol, Rt(min) 3.787; FIA ES+ 241.8, ES− not observed).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][OH:20])[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2]>ClCCl.[O-2].[O-2].[Mn+4]>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH:19]=[O:20])[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cc(CO)cc(-c2cccc(C#N)c2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)c1cc(C=O)cc(-c2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 85.2 %

Procedure:
In 200 ml of dichloromethane, was dissolved 9.05 g of the compound obtained in Example 1, 2 or 3. To the resulting solution, was added 20.6 g of manganese dioxide. The obtained mixture was stirred at room temperature for 40 hours. The reaction solution was filtered through Celite, and the Celite was further washed with dichloromethane. Each filtrate was combined into one portion, and the solvent was removed under reduced pressure to afford 7.65 g (85%) of the title compound as a white crystal.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[C:29]([C:30](O)=[O:31])=[C:28]([CH3:33])[O:27][N:26]=1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:30]([C:29]2[C:25]([CH3:24])=[N:26][O:27][C:28]=2[CH3:33])=[O:31])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1noc(C)c1C(=O)O
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)noc2C)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 3,5-Dimethyl-isoxazole-4-carboxylic acid. LC-MS (basic): tR=0.87 min; [M+H]+=471.3.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][OH:13])=[O:8])=[CH:5][CH:4]=1.[CH2:18]([O:25][C:26]1[CH:31]=[C:30]([Cl:32])[C:29](O)=[C:28]([Cl:34])[CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([Cl:34])[C:29]([O:13][CH2:12][CH2:11][CH2:10][NH:9][C:7](=[O:8])[C:6]2[CH:14]=[CH:15][C:3]([C:2]([F:16])([F:17])[F:1])=[CH:4][CH:5]=2)=[C:30]([Cl:32])[CH:31]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: O=C(NCCCO)c1ccc(C(F)(F)F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl)c1ccc(C(F)(F)F)cc1

Procedure:
A reaction vessel was charged with 5.25 g (21.2 mmol) of 3-(4-(trifluoromethyl)benzamido)propan-1-ol, 5.72 g (21.2 mmol) of 4-benzyloxy-2,6-dichlorophenol, 5.29 g (20.2 mmol) of triphenylphosphine and 100 ml of tetrahydrofuran, and a solution of 4.08 g (20.2 mmol) of diisopropyl azodicarboxylate dissolved in 20 ml of tetrahydrofuran was added dropwise, while stirring. After stirring at room temperature for 12 hours, the reaction mixture was concentrated, and the residue was subjected to silica gel chromatography, which afforded 1-benzyloxy-3,5-dichloro-4-(3-(4-trifluoromethylbenzamido)propyloxy)benzene.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.CN(CCN(C)C)C.[Li]C(CC)C.[C:31](=[O:33])=[O:32]>CCOCC.O>[CH3:15][C:14]([O:13][C:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[C:10]=2[C:31]([OH:33])=[O:32])[CH2:6][CH2:7]1)=[O:12])([CH3:17])[CH3:16]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(F)cc21
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(F)c(C(=O)O)c21
Temperature: -78 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a stirred solution of 1,1-dimethylethyl 6-fluoro-2,3-dihydro-1H-indole-1-carboxylate (8.7 g, 0.037 mol) in Et2O (150 mL) at −78° C. was added TMEDA (7.2 mL, 0.048 mol) and a solution of 1M sec-BuLi (44 mL, 0.044 mol) dropwise. The reaction mixture was stirred for 1 h at −78° C. and then poured onto crushed CO2 (250 mL). The mixture was allowed to warm to room temperature overnight. The suspension was diluted with water (200 mL) and diethyl ether (50 mL), and the layers were separated. The aqueous fraction was acidified with 1M HCl and extracted with diethyl ether (3×100 mL). The combined organic layers were washed with brine (1×50 mL), dried (Na2SO4), and concentrated under reduced pressure giving 8.0 g (77%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:9]1[C:10]([C:16](O)=[O:17])=[N:11][C:12]([CH3:15])=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=1>>[C:1]([O:5][C:6](=[O:7])[N:8]([C:9]1[C:10]([C:16](=[O:17])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=2)=[N:11][C:12]([CH3:15])=[CH:13][N:14]=1)[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1ccc(F)cn1
Reactant: Cc1cnc(N(C(=O)OC(C)(C)C)c2cccnc2)c(C(=O)O)n1
Product: Cc1cnc(N(C(=O)OC(C)(C)C)c2cccnc2)c(C(=O)Nc2ccc(F)cn2)n1

Procedure:
The title compound, MS: m/e=425.2 (M+H+), was prepared in accordance with the general method of example 8, step 3 from 3-(tert-butoxycarbonyl-pyridin-3-yl-amino)-6-methyl-pyrazine-2-carboxylic acid and 2-amino-5-fluoropyridine.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:43])[NH2:42])[CH:37]=2)[CH:32]=1)(=O)=O.C(OCC)C>N1C=CC=CC=1>[C:1]1([CH2:7][C:8]([O:10][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:42])[NH2:43])[CH:37]=3)[CH:32]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: O=C(O)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)Cc3ccccc3)ccc2c1
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
To a solution of 2.4 g of phenylacetic acid in 50 ml of anhydrous pyridine, while being cooled and stirred, was added 4.4 g of DCC. After 30 minutes, to the mixture was added 5.0 g of 6-amidino-2-naphthol methanesulfonate. The mixture was stirred at room temperature for 24 hours, mixed with ethyl ether, and the precipitate was collected by filtration. The precipitate was dissolved in DMF and the insolubles were filtered off. The filtrate containing the DMF-soluble substances was mixed with ethyl ether, the resulting precipitate was collected by filtration and recrystallized from a mixture of DMF and ethyl ether to obtain 3.0 g of a white powder of 6-amidino-2-naphthyl phenylacetate methanesulfonate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][O:25][CH2:24]2)[CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1>>[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:19]([C:16]2[S:15][C:11]3[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[O:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][O:25][CH2:24]4)[C:10]=3[C:17]=2[CH3:18])=[O:20])[CH2:32][CH2:31]1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCOC3)c12
Reactant: CN1CCC(N)CC1
Product: Cc1c(C(=O)NC2CCN(C)CC2)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCOC3)c12

Procedure:
Prepared analogously to example 10.4 from 4-{4-fluoro-2-[(R)-(tetrahydro-pyran-3-yl)oxy]-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and 1-methyl-piperidin-4-ylamine.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[N:14]=[N:13][CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(CCN(C)C)C.[Li]CCCC.[Sn:28](Cl)([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32]>C(OCC)C.O>[CH2:1]([O:8][CH2:9][N:10]1[N:14]=[N:13][C:12]([Sn:28]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:29][CH2:30][CH2:31][CH3:32])=[N:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1ccc(COCn2ncnn2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1nnn(COCc2ccccc2)n1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To. a solution of 2-benzyloxymethyltetrazole (1 mmole) and TMEDA (2 mmole) in 3 mL diethyl ether at −78° C. was added n-BuLi in hexanes (1 mmole). This was let stir for 5 min at −78° C. and then it was added to a precooled (−78° C.) solution of (n-Bu)3SnCl (1 mmole) in 2 mL of diethyl ether. After stirring at −78° C. for 30 min it was diluted with water and diethyl ether. Extraction and chromatography provided 2-benzyloxymethyl-5-(tributylstannyl)tetrazole as a colorless oil.
Reaction SMILES: C([O:8][CH2:9][CH:10]([O:34][CH3:35])[CH2:11][S:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])C1C=CC=CC=1.C[Si](I)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+].ClCCl>C(#N)C>[CH2:15]([NH:14][C:13]([S:12][CH2:11][CH:10]([O:34][CH3:35])[CH2:9][OH:8])=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)SCC(COCc1ccccc1)OC
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)SCC(CO)OC
Reaction time: 15 h
Yield: 57.2 %

Procedure:
To a solution of 1.02 g (2 mM) of 3-benzyloxy-2-methoxy-1-octadcylcarbamoylthiopropane VI a6 in 80 ml of acetonitrile is added 0.4 ml (2.81 mM) of trimethylsilyl iodide with ice-cooling and the mixture is allowed to stand at room temperature for 15 hours. To the reaction mixture is added 50 ml of 10% aqueous solution of sodium thiosulfate and the product is isolated with dichloromethane extraction. The dichloromethane layer is washed with water, dried, and evaporated. The residue is purified by column chromatography on silica gel using a n-hexane-ethyl acetate (2:1) mixture as an eluent to give 480 mg (1.15 mM) of the titled compound, 3-octadecylcarbamoylthio-2-methoxypropylalcohol V a6 as a solid in 57% yield.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O-])(O)=O.[Na+].[C:16]1(C)C=CC=C[CH:17]=1>N1C=CC=CC=1>[CH2:8]([CH:9]1[CH2:10][CH2:5][CH:3]=[CH:2][O:1]1)[CH2:7][CH:6]=[CH:16][CH3:17]
Reactant: O=C(CO)c1ccccc1
Reactant: Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC=CCCC1CCC=CO1

Procedure:
The acetyl derivative derived from the fragrant lactone (5 mmol) and pyridine (3-4 drops, 0.1 eq.) was added to a suspension of the hydroxy-acetophenone (10 mmol) in toluene (10 ml) The mixture was heated under reflux overnight. It was then poured into aq. NaHCO3 (sat.) and the separated aqueous phase was extracted with MTBE. The combined organic layers were washed with brine and dried over MgSO4. The crude, obtained after evaporation of the solvents, was purified by chromatography (SiO2, EtOAc/Hexane) to afford the desired product as a colorless to pale yellow oil.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([OH:16])=[O:15])[C:12]=1[NH2:20]>O>[C:2]1([C:1]2[O:10][C:11]3[C:12](=[C:13]([C:14]([OH:16])=[O:15])[CH:17]=[CH:18][CH:19]=3)[N:20]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1c(O)cccc1C(=O)O
Solvent: O
Product: O=C(O)c1cccc2oc(-c3ccccc3)nc12
Temperature: 180 °C
Reaction time: 2 h

Procedure:
Benzoic acid (122 mg, 1.0 mmol) and 3-hydroxyanthranilic acid (153 mg, 1.0 mmol) were added to PPA (1 g), the mixture was stirred at 180° C. for 2 hr. After cooled to room temperature, water (50 mL) was added and filtered; the cake was washed with water and dried in vacuum to obtain 2-phenylbenzo[d]oxazole-4-carboxylic acid. LC-MS (ESI) m/z 240 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([Cl:15])=[O:11])[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc(C(=O)O)n1
Solvent: ClCCl
Product: COc1cccc(C(=O)Cl)n1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a mixture of 5.00 g (32.7 mmol) 6-methoxy-pyridine-2-carboxylic acid in 100 mL DCM was added 40.8 mL (81.6 mmol) 2 M oxalyl chloride solution in DCM and stirred at 40° C. for 2 h. The solvent was removed by distillation.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4.[CH3:24][O:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(N(C)C)=O>[CH3:24][O:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29][O:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4
Reactant: COC(=O)CCCBr
Reactant: CC1(C)c2ccc(O)cc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)CCCOc1ccc2c(c1)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
9-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound J5, 30 mg, 0.099 mmol), 4-bromo-butyric acid methyl ester (24.9 μl, 0.198 mmol) and cesium carbonate (64.5 mg, 0.198 mmol) were dissolved in DMA (0.20 ml) and stirred at room temperature for 4 hr. Water was added to the reaction solution, which was then extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The yellow solid obtained after concentration under reduced pressure was purified by silica gel column chromatography (methylene chloride/MeOH) to obtain 4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl oxy)-butyric acid methyl ester as an intermediate.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[CH2:24]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25]#[CH:26]>>[O:27]([CH2:24][C:25]1[N:1]([CH:4]2[CH2:23][N:8]3[C:9]4[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]3[CH2:6][CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:2]=[N:3][CH:26]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CCOc1ccccc1
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1nncc1COc1ccccc1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 3 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and (prop-2-yn-1-yloxy)benzene. MS (+ESI) m/z: 403.1.