Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][CH2:4][N:5]1[CH2:24][CH2:23][C:8]2([NH:12][C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)[C:9]2=[O:22])[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH2:38]([S:40]([Cl:43])(=[O:42])=[O:41])[CH3:39]>CN(C=O)C>[ClH:43].[Br:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:10]2[C:9](=[O:22])[C:8]3([CH2:7][CH2:6][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:24][CH2:23]3)[NH:12][C:11]2=[O:13])=[CH:16][CH:17]=1
Reactant: CCS(=O)(=O)Cl
Reactant: N[C@@H](CCN1CCC2(CC1)NC(=O)N(Cc1ccc(Br)cc1)C2=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N[C@@H](CCN1CCC2(CC1)NC(=O)N(Cc1ccc(Br)cc1)C2=O)c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.5 %

Procedure:
To a solution of 8-(3-(S)-amino-3-phenylpropyl)-3-(4-bromobenzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione (60 μmol) in anhydrous DMF (1 mL) was added triethylamine (10 μL, 72 μmol) and ethane sulfonyl chloride (68 μL, 72 μmol). The reaction mixture was agitated overnight at room temperature and then concentrated in vacuo. The residue was purified by semi-preparative HPLC (Method D) and lyophilized to give the Compound 94 as a colorless solid (4.5 mg, 13%).
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:10]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:12][CH2:13]C)=[O:11]>C1(C)C=CC=CC=1>[C:10]([O:12][CH3:13])(=[O:11])/[CH:15]=[CH:2]/[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCCC=O
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/CCCC(=O)OC
Yield: 48 %

Procedure:
A solution of methyl 5-oxopentanoate (1.9 g, 14.6 mmol) and (carboethoxymethylene) triphenylphosphorane (5.0 g, 14.9 mmol) in toluene (50 mL) was refluxed for 8 hours. Solvent was removed under vacuo and the crude was purified by flash chromatography on silica gel (eluant: AcOEt/hexane 2/8) to give 1.32 g (48% yield) as colorless oil of the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][CH2:4][CH:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)[OH:6].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>COC(C)(C)C>[F:1][C:2]([F:18])([F:19])[CH2:3][CH2:4][CH:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)[O:6][S:28]([CH3:27])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(C(O)CCC(F)(F)F)cc1
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C(CCC(F)(F)F)OS(C)(=O)=O)cc1
Reaction time: 1 h

Procedure:
To a solution of ethyl(+/−)-4-(4,4,4-trifluoro-1-hydroxybutyl)benzoate (264 mg, 0.956 mmol) in tert-butyl methyl ether (4.8 mL) was added triethylamine (0.201 mL, 1.43 mmol), followed by methanesulfonyl chloride (0.091 mL, 1.15 mmol). The resulting mixture was stirred for 1 hour. Then, the reaction mixture was diluted with tert-butyl methyl ether (25 mL) and washed with water (15 mL), sat. aq sodium bicarbonate (15 mL), then sat. aq sodium chloride (15 mL). The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure to give ethyl(+/−)-4-(4,4,4-trifluoro-1-((methylsulfonyl)oxy)butyl)benzoate. This material was used without further purification. 1HNMR (400 MHz, CDCl3) δ 8.12 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.2 Hz, 2H), 5.63 (dd, J=7.9, 4.8 Hz, 1H), 4.41 (q, J=7.0 Hz, 2H), 2.77 (s, 3H), 2.39-2.08 (m, 4H), 1.41 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N:1]1([C:7]2[C:8](OS(C(F)(F)F)(=O)=O)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:29]1[C:33](B(O)O)=[CH:32][C:31]2[CH:37]=[CH:38][CH:39]=[CH:40][C:30]1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:29]1[C:33]([C:8]2[C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=3)[N:9]=2)=[CH:32][C:31]2[CH:37]=[CH:38][CH:39]=[CH:40][C:30]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCC3)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc4ccccc4s3)c(N3CCCCC3)nc2c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(piperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (280 mg, crude) in dioxane (5 mL) was added benzo[b]thiophen-2-ylboronic acid (357 mg, 2.0 mmol), K3PO4 (425 mg, 2.0 mmol), Pd(PPh3)4 (39 mg, 0.033 mmol) and water (3 drops). The resulting solution was stirred for 1 h at 90° C. and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 3.3% ethyl acetate in petroleum ether to afford methyl 2-(benzo[b]thiophen-2-yl)-3-(piperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (100.0 mg, 37% 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[F:13].[CH3:14][NH:15][CH2:16]C(O)=O.[CH2:20]=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:9]([N+:10]([O-:12])=[O:11])[CH2:20][N:15]([CH3:16])[CH2:14]2)=[CH:4][C:3]=1[F:13]
Reactant: C=O
Reactant: CNCC(=O)O
Reactant: O=[N+]([O-])/C=C/c1ccc(Cl)c(F)c1
Solvent: Cc1ccccc1
Product: CN1C[C@@H]([N+](=O)[O-])[C@H](c2ccc(Cl)c(F)c2)C1
Reaction time: 8 h
Yield: 45 %

Procedure:
(E)-1-chloro-2-fluoro-4-(2-nitrovinyl)benzene (4.2 g, 20.84 mmol), 2-(methylamino)acetic acid (4.64 g, 52.1 mmol), paraformaldehyde (3.75 g, 125 mmol) were mixed in dry toluene (104 mL). The reaction mixture was heated at reflux using Dean-stark overnight. The reaction mixture was partitioned between EtOAc and water. The organic was washed by sat. NaCl, dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography to yield (+/−)-(3R,4S)-3-(4-chloro-3-fluorophenyl)-1-methyl-4-nitropyrrolidine in 45% yield. LCMS (m/z): 259.2 (MH+), 0.52 min; 1H NMR (400 MHz, CDCl3) δ ppm 7.37 (t, J=8.0 Hz, 1H), 7.15 (dd, J=2.0, 10.2 Hz, 1H), 7.09-7.01 (m, 1H), 4.91-4.82 (m, 1H), 3.98 (d, J=5.1 Hz, 1H), 3.34 (dd, J=4.1, 10.8 Hz, 1H), 3.23 (t, J=8.6 Hz, 1H), 3.10 (dd, J=7.8, 10.6 Hz, 1H), 2.63 (dd, J=7.0, 9.4 Hz, 1H), 2.44 (s, 3H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].I[CH:8]([CH3:10])[CH3:9].[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[C:21]([OH:27])[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C.O>[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[C:21]([O:27][CH:8]([CH3:10])[CH3:9])[CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cc(OCc2ccccc2)ccc1C=O
Temperature: 50 °C

Procedure:
K2CO3 (9.62 g, 69.6 mmol) and 2-iodopropane (2.00 mL, 20.00 mmol) were added successively to a stirred solution of 4-benzyloxy-2-hydroxybenzaldehyde (3.65 g, 16.0 mmol) in dry DMF (20.0 mL) at 25° C. under N2. The reaction was heated at 50° C. overnight. The reaction was diluted with water (50 mL) and extracted with Et2O (3×50 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford 4-(benzyloxy)-2-isopropoxybenzaldehyde. LCMS calc.=293.1; found=292.9 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O1CCCC1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]#[C:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Brc1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.3 %

Procedure:
28.3 g (0.10 mol) of p-bromoiodobenzene, 10.2 g (0.10 mol) of phenylacetylene, 701 mg (1 mmol) of bis(triphenylphosphine)palladium(II)dichloride, and 190 mg (1 mmol) of copper (I) iodide were placed in a 1000-mL three-neck flask, and nitrogen substitution was carried out. Then, 350 mL of tetrahydrofuran and 18 mL of triethylamine were added thereto, and the mixture was stirred at room temperature for 12 hours. After the reaction, the reaction mixture washed with a 3% hydrochloric acid aqueous solution, and the aqueous phase was extracted with ethyl acetate. The extracted solution combined with the organic phase washed with brine and dried with magnesium sulfate. The mixture was filtered through celite, florisil, and alumina, and a solid obtained by the concentration of the filtrate was recrystallized with hexane to give 15 g of a solid that was the target substrate in the yield of 58%.
Reaction SMILES: C(O[C:4](=[O:25])[CH2:5][C:6]1[N:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:10]=1)C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:29]=1.O>CN1C(=O)CCC1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([N:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=[C:6]2[CH2:5][C:4]([N:37]2[CH2:38][CH2:39][N:34]([C:30]3[CH:29]=[C:28]([O:27][CH3:26])[CH:33]=[CH:32][N:31]=3)[CH2:35][CH2:36]2)=[O:25])=[CH:19][CH:20]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(F)cc2)cn1-c1ccc(F)cc1
Reactant: COc1ccnc(N2CCNCC2)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccnc(N2CCN(C(=O)Cc3nc(-c4ccc(F)cc4)cn3-c3ccc(F)cc3)CC2)c1
Yield: 31 %

Procedure:
70 mg (1,4-bis-(4-fluoro-phenyl)-1H-imidazol-2-yl)-acetic acid ethyl ester, 58 mg 1-(4-methoxy-pyridin-2-yl)-piperazine and 0.05 mLN,N-diisopropylethylamine in 2 mL NMP was stirred 50 min. at 180° C. under microwave condition. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was purified by HPLC (column: Waters Symmetry 50×140 mm 7 μm, mobile layer: water+0.3% HCOOH/methanol 10% until 90% in 14 min) to give 31 mg desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=[C:9]2[C:17]([OH:19])=[O:18])([O-:3])=[O:2].[CH2:20](O)[CH3:21]>Cl>[CH2:20]([O:18][C:17]([C:9]1[C:8]2[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1)=[O:19])[CH3:21]
Reactant: O=C(O)c1ccc(C(=O)O)c2c([N+](=O)[O-])cccc12
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(C(=O)O)c2c([N+](=O)[O-])cccc12

Procedure:
52 parts of 8-nitro-naphthalene-1,4-dicarboxylic acid are dissolved in 700 parts of absolute ethyl alcohol and the solution is boiled under reflux for 12 hours whilst continuously passing in hydrogen chloride gas. The resulting solution is evaporated in vacuo. The 4-ethoxycarbonyl-8-nitro-naphthalene-1-carboxylic acid of the formula ##STR15## which is obtained in this way, melts at 178° to 180°.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:14][S:15](O)(=[O:17])=[O:16]>>[Cl:14][S:15]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[C:1]2[C:11]([OH:13])=[O:12])(=[O:17])=[O:16]
Reactant: O=C(O)c1cccc2ccccc12
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1cccc2c(S(=O)(=O)Cl)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
The titled compound was prepared using a modified procedure of Reefschlager et al. (see Reefschlager, J., et al., (2000) EP1038868A2). Naphthalene-1-carboxylic acid (6.56 g, 38.1 mmol) was added in small portions to chlorosulfonic acid (22 g, 12.6 mL, 190 mmol) that was cooled in an ice bath. The reaction was stirred overnight at room temperature. The reaction mixture was poured slowly over ice-water (250 mL) and filtered to afford 45 (8.3 g, 80%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 14.0 (s, 1H), 9.11 (d, 1H), 8.80 (d, 1H), 8.08 (d, 1H), 8.00 (d, 1H), 7.56 (m, 2H).
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.C(N=C=N)C.[CH2:38]([N:45]1[CH2:49][C@H:48]2[C@H:50]([NH2:53])[CH2:51][CH2:52][C@H:47]2[CH2:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[CH2:38]([N:45]1[CH2:49][C@H:48]2[C@H:50]([NH:53][C:8](=[O:10])[C@@H:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:51][CH2:52][C@H:47]2[CH2:46]1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: CC(C)C[C@@H](C(=O)O)N1CCCS1(=O)=O
Agent: CCN=C=N
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N1CCCS1(=O)=O
Reaction time: 0.25 h

Procedure:
(2S)-2-(1,1-Dioxidoisothiazolidin-2-yl)-4-methylpentanoic acid (359 mg, 1.526 mmol) was combined with triethylamine (0.387 mL, 2.77 mmol) in dichloromethane (10 mL). 1-Hydroxybenzotriazole (234 mg, 1.526 mmol) and N43-dimethylaminopropyl)-N′-ethylcarbodiimide (0.270 mL, 1.526 mmol) were added, and the reaction mixture was stirred for 15 minutes. Then (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine (300 mg, 1.387 mmol) from Example 16 Step E was added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched with 10 mL of aqueous sodium bicarbonate and extracted with 3×20 mL of dichloromethane. The solvent was removed in vacuo. The crude material was applied to a silica gel cartridge (Analogix®, Burlington, Wis., RS15-24) and eluted with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.76 (d, J=6.9, 1H), 7.46-7.39 (m, 2H), 7.40-7.33 (m, 2H), 7.26 (dd, J=9.9, 17.2, 1H), 4.52 (t, J=7.7, 1H), 4.44-4.34 (m, 1H), 3.93 (dt, J=7.0, 14.5, 1H), 3.57 (dd, J=5.4, 13.1, 1H), 3.49-3.36 (m, 2H), 3.30-3.20 (m, 2H), 2.83-2.74 (m, 1H), 2.62-2.45 (m, 2H), 2.44-2.37 (m, 1H), 2.33-2.17 (m, 4H), 2.11 (qd, J=6.5, 12.5, 1H), 1.92-1.78 (m, 3H), 1.77-1.59 (m, 2H), 1.45-1.32 (m, 1H), 0.88 (d, J=6.6, 3H), 0.83 (dd, J=2.5, 6.5, 3H); MS (ESI+) m/z 434 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16]([OH:18])=O)[CH:9]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[NH2:29][C:30]1([C:41]([O:43][CH3:44])=[O:42])[CH2:35][CH2:34][C:33]([O:39][CH3:40])([CH2:36][O:37][CH3:38])[CH2:32][CH2:31]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16]([NH:29][C:30]3([C:41]([O:43][CH3:44])=[O:42])[CH2:31][CH2:32][C:33]([O:39][CH3:40])([CH2:36][O:37][CH3:38])[CH2:34][CH2:35]3)=[O:18])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COCC1(OC)CCC(N)(C(=O)OC)CC1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: COCC1(OC)CCC(NC(=O)Cc2cc(-c3ccc(Cl)cc3)ccc2C)(C(=O)OC)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
574 mg (2.20 mmol) of (4′-chloro-4-methylbiphenyl-3-yl)acetic acid (EP 2029531 A1 and US 2009/298828 A1) were dissolved in 0.9 g (12.5 mmol) of thionyl chloride. The reaction mixture was stirred at 80° C. for 1 h and then concentrated. The residue was dissolved in 5 ml of acetonitrile. 816 mg (5.90 mmol) of potassium carbonate were added to 390 mg (1.69 mmol) of the compound from Example 24A in 10 ml of acetonitrile. With ice-cooling, the solution of the acid chloride was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was then concentrated, the residue was taken up in ice-water and extracted repeatedly with dichloromethane, and the combined organic phases were washed repeatedly with 1N aqueous hydrogen chloride solution and saturated aqueous sodium bicarbonate solution, dried over sodium sulphate, filtered and concentrated. This gave 570 mg of the title compound as a diastereomer mixture which were reacted without further purification.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[NH:12][C:13]2[C:18]([C:19](=O)[N:20]=1)=[C:17](OC)[C:16](OC)=[C:15](OC)[CH:14]=2.Cl[C:29]1C=C[N:32]=[C:31](CNC)[CH:30]=1>CCO>[CH:19]1[C:18]2[C:17]3[CH:29]=[CH:30][CH:31]=[N:32][C:16]=3[CH:15]=[CH:14][C:13]=2[N:12]=[CH:11][N:20]=1
Reactant: COc1cc2[nH]c(Cl)nc(=O)c2c(OC)c1OC
Reactant: CNCc1cc(Cl)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: c1cnc2ccc3ncncc3c2c1
Temperature: 90 °C

Procedure:
Diisopropylethylamine (0.15 mL, 0.86 mmol) was added to a mixture of 2-chloro-5,6,7-trimethoxy-1H-quinazolin-4-one (0.2 g, 0.78 mmol) and 4-chloro-2-methylaminomethylpyridine (0.13 g, 0.86 mmol) in EtOH (8 mL). The mixture was heated at 90° C. for 5 h. After cooling, the resulting white solid was filtered and washed with MeOH to provide quinazolino-pyridine compound.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=3)[C:16]=2[O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:30][CH:29]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:46]>CN(C)C=O>[C:1]([N:5]([CH3:46])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=3)[C:16]=2[O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]3)=[CH:30][CH:29]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(=O)(=O)NC(C)(C)C)cc3)ccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(=O)(=O)N(C)C(C)(C)C)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 599.8 %

Procedure:
To a stirring room temperature solution of the product of Example 62 (79 mg, 0.013 mmol) in dimethylformamide (5 mL) add 60% sodium hydride (6 mg, 0.15 mmol). Stir this mixture at ambient temperature for 10 minutes and then add iodomethane (0.014 mL, 0.15 mmol). Stir the reaction for 30 minutes at ambient temperature then quench it with brine. Extract the resulting aqueous mixture into ethyl acetate. Wash the combined extracts with brine; dry (sodium sulfate) and concentrate them in vacuo. Purify the resulting material on a Chromatotron (silica gel; 3%-10% MeOH gradient in CH2Cl2) to obtain 47 mg of the title compound (68%). MS (IS+) m/e 603 (M+1).
Reaction SMILES: Cl.[S:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.Br[CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])[C:13]([OH:15])=[O:14].[OH-].[K+].Cl>O.CO>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:12]([N:7]1[CH2:8][CH2:9][C:10]2[S:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)C(Br)c1ccccc1Cl
Reactant: c1cc2c(s1)CCNC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 40 °C
Yield: 93.3 %

Procedure:
50.0 g of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride and 74.6 g of α-bromo-(2-chlorophenyl)acetic acid were successively added to a mixture of 275 ml of water and 75 ml of methanol, and the resulting solution was cooled to below 10° C. while stirring. 63.9 g of 85.0% KOH dissolved in 142 ml of water was slowly added to the above solution while maintaining the temperature at below 15° C. The resulting transparent solution was heated to 40° C. and stirred at that temperature for 3 hrs. The pH of the reaction solution was adjusted to 3.5 with 6N-HCl, cooled to room temperature and stirred for 2 hrs. Then, the reaction mixture was further cooled to below 5° C. and stirred for 2 hrs. The precipitated crystals were filtered, washed sequentially with 150 ml of water and 100 ml of n-hexane, and dried at 40° C. to obtain 81.7 g of the title compound (yield: 88%) as a white-yellow monohydrate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:20]=CC=C[CH:16]=1.CC(O)C.C(OC(N=NC(OC(C)C)=O)=O)(C)C>C1COCC1>[CH:15]([O:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])([CH3:20])[CH3:16]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
Methyl 2-hydroxy-5-nitrobenzoate (11.82 g, 60 mmol), triphenylphosphine (17.29 g, 66 mmol) and iPrOH (3.96 g, 5 ml, 66 mmol) were taken up in THF (150 ml) and cooled in ice. Di-isopropyl-azodicarboxylate (8.31 g, 10 ml, 66 mmol) was added carefully, and the reaction was stirred at RT overnight. The volatiles were removed in vacuo and the residue treated with EtOAc (50 ml). The solids that didn't dissolve were removed by filtration, and the filtrate evaporated to dryness in vacuo. The residue was purified by column chromatography to give methyl 2-isopropoxy-5-nitrobenzoate (6.92 g, 48.5%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][OH:27])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][O:27][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCO)ccc23)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCOS(C)(=O)=O)ccc23)CC1
Reaction time: 4 h

Procedure:
To a mixture of 4-[7-(2-hydroxy-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (90 mg, 0.24 mmol) and DIPEA (167.2 μL) in CH2Cl2 (5 mL) was added MsCl (37.2 μL). The reaction mixture was stirred for 4 h and the solvents were evaporated. The residue was purified by flash column chromatography on silica gel (EtOAc as eluent) to afford almost pure product. 1H NMR (CDCl3) δ 9.15 (s, 1H), 8.09 (d, J=9.33 Hz, 1H), 7.33 (d, J=2.44 Hz, 1H), 7.29 (dd, J=9.18 and 2.59 Hz, 1H), 4.66 (t, J=4.29 Hz, 2H), 4.42 (t, J=4.39 Hz, 2H), 4.33 (m, 2H), 3.61 (m, 1H), 3.11 (s, 3H), 2.94 (m, 2H), 1.83-2.10 (4H), 1.48 (s, 9H). Calcd for C21H30N3O6S (MH+) 452.2, found 452.2.
Reaction SMILES: N1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2N=CC=C3)C=CC=1.[C:15]([O-:18])([O-])=O.[Cs+].[Cs+].IC1[CH:23]=[C:24]([O:28]C)C=CC=1>[Cu]I.C(O)C>[CH2:24]([O:28][C:14]1[CH:13]=[C:8]([O:18][CH3:15])[CH:7]=[CH:6][CH:5]=1)[CH3:23]
Reactant: COc1cccc(I)c1
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [Cs+]
Solvent: CCO
Product: CCOc1cccc(OC)c1
Temperature: 110 °C
Reaction time: 20 h
Yield: 466.5 %

Procedure:
A test tube was charged with CuI (20 mg, 0.10 mmol, 10 mol %), 1,10-phenanthroline (36 mg, 0.20 mmol, 20 mol %), Cs2CO3 (456 mg, 1.4 mmol), 3-iodoanisole (119 μL, 1.0 mmol) and ethanol (1.0 mL). The test tube was sealed and the reaction mixture was stirred at 110° C. for 20 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with diethyl ether. The filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (2×20 cm; pentane/diethyl ether 30:1) provided 142 mg (93% yield) of the title compound as a colorless oil.