Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(NC(C2(C)CCC3C(C)=C(OC(=O)C)C(C)=C(C)C=3O2)=S)C=CC=CC=1.[C:28]1([NH:34][C:35]([C:37]2([CH3:55])[CH2:42][CH2:41][C:40]3[CH:43]=[C:44]([O:51]C(=O)C)[C:45]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:46][C:39]=3[O:38]2)=[S:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([NH:34][C:35]([C:37]2([CH3:55])[CH2:42][CH2:41][C:40]3[CH:43]=[C:44]([OH:51])[C:45]([C:47]([CH3:49])([CH3:48])[CH3:50])=[CH:46][C:39]=3[O:38]2)=[S:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(C(=S)Nc1ccccc1)CC2
Agent: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=S)Nc1ccccc1)O2
Product: CC1(C(=S)Nc2ccccc2)CCc2cc(O)c(C(C)(C)C)cc2O1

Procedure:
By carrying out the reaction as in Example 2 (2nd process), but replacing the compound of Example 1 with the compound of Example 73, the title product is obtained.
Reaction SMILES: C([O:3][C:4](=[O:41])[C@@H:5]([NH:10][C:11](=[O:40])[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][CH2:25][C@H:26]([OH:39])[C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:28]=3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[Na+]>>[OH:39][C@H:26]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:28]=1)[CH2:25][NH:24][CH:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([NH:10][C@@H:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:41])=[O:3])=[O:40])=[CH:13][CH:14]=2)[CH2:19][CH2:20]1
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C[C@H](NC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from 2-(4-(4-{2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-4-methyl-pentanoic acid ethyl ester (which was obtained in Example 198) by sodium hydroxide hydrolysis as a white solid; mp>177° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 0.87 (d, J=6.3 Hz, 3 H) 0.90(d, J=6.3 Hz, 3 H), 1.35–1.75 (m, 5 H), 1.90–2.00 (m, 2 H), 2.60–2.90 (m, 5 H), 2.94 (s, 3 H), 3.65–3.80 (m, 2 H), 4.25–4.35 (m, 1 H), 4.60–4.65 (m, 1 H), 6.85 (d, J=8.3 Hz, 1 H), 6.90 (d, J=8.9 Hz, 2 H), 7.05 (dd, J=8.3, 1.9 Hz, 1 H), 7.21 (d, J=1.9 Hz, 1 H), 7.73 (d, J=8.9 Hz, 2 H), 7.98 (d, J=7.7 Hz, 1 H); MS(ES) m/z: 561.3 (M−H)−; HRMS Calcd. for C27H37N4O7S (M−H)−: 561.2377. Found: 561.2381.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6](O)[C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1.[CH3:12][C:13](=[CH:15][CH2:16][CH2:17][CH:18]([CH2:20][CH:21]=O)[CH3:19])[CH3:14]>>[CH3:19][CH:18]([CH2:17][CH2:16][CH:15]=[C:13]([CH3:14])[CH3:12])[CH2:20][CH:21]=[CH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: CC(C)=CCCC(C)CC=O
Product: CC(C)=CCCC(C)CC=Cc1ccc(C(C)C)cc1
Yield: 82 %

Procedure:
To a stirred solution of sodium (21 g, 0.9 at) in 1500 ml of absolute ethanol was added 388 g of p-isopropylbenzyltriphenylphosphonium chloride. The resulting phosphorane solution was cooled to 15°-20° C. (The light orange color fades when the temperature is lowered!) Freshly vacuum distilled citronellal (150 g, 1 mol.) was added dropwise while keeping the reaction mixture at reflux for 4 hours. The cooled reaction mixture was filtered to remove sodium chloride, most of the alcohol was distilled off in vacuo and 500 ml of hexane was added. The triphenylphosphineoxide was allowed to crystallize and filtered off. The solvents were removed from the mother liquors under vacuum and another 500 ml of hexane added. Cooling afforded another crop of triphenylphosphineoxide. The hexane was again evaporated and the residue distilled yielding, after a small forerun of isopulegol (a contaminant of citronellal), 200 g (82%) of the desired product. bp. 150°-145° C/0.1 mm. Ratio of E to Z is app. 40:60. nD25 = 1.5172
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[C:11]2[CH:16]=[CH:15][C:14]([O: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][CH3:31])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.[Br-:45].[Li+]>O1CCCC1.O>[Br:45][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[C:11]2[CH:16]=[CH:15][C:14]([O: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][CH3:31])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Nc2cccc(CO)c2)cc1
Reactant: [Br-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Nc2cccc(CBr)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-[3-(hydroxymethyl)phenyl]-4-(tetradecyloxy)benzamide and 3.47 g of methanesulfonyl chloride in 200 ml of tetrahydrofuran is added 3.07 g of triethylamine followed by stirring at ambient temperature for 2 hours. Also added is 21.93 g of lithium bromide followed by stirring at ambient temperature for an additional 3 hours. The mixture is poured into water and extracted with ether. The organic layer is washed with a mixture of brine and saturated sodium bicarbonate then dried. The solvent is removed under vacuum and the residue crystallized from carbon tetrachloride:hexanes to give the desired product as a white solid, m.p. 116°-118° C.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:31]=[CH:30][S:29][CH:28]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:31]=[CH:30][S:29][CH:28]=3)[C:25]2=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: O=C=Nc1ccsc1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccsc3)c(=O)n(C3CCCC3)c12

Procedure:
1-Cyclopentyl-7-methoxy-3-thiophen-3-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione (21 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1. mmol) and 3-isocyanato-thiophene (0.5 mmol) following general procedure C. LCMS: m/z 394 [M+1]+.
Reaction SMILES: [Na].[OH:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.Br[CH2:11][CH3:12]>C(O)C>[CH2:11]([O:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:12]
Reactant: CCBr
Reactant: Cc1ncccc1O
Agent: [Na]
Solvent: CCO
Product: CCOc1cccnc1C

Procedure:
Sodium metal (46.2 g) was dissolved in absolute ethanol (1 l) with stirring under nitrogen. 3-Hydroxy-2-methylpyridine (200 g prepared as described in C.A. 48, P4597 h) was added. The mixture was stirred at ambient temperature for 30 minutes and then a solution of bromoethane (150 ml) in absolute ethanol (100 ml) was added. The mixture was boiled under reflux for 5 hours then cooled and filtered. The filtrate was evaporated and the residue partitioned between dichloromethane and water. The organic layer was separated off and the aqueous layer extracted with dichloromethane. The combined organic extracts were dried and evaporated. The residue was distilled to give 3-ethoxy-2-methyl-pyridine b.p. 80°-84° C. (20 mmHg).
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:38](OC)[O:39]C)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O>O>[CH2:1]([S:8][CH:9]([CH:38]=[O:39])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:30])=[O:31])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(SCc3ccccc3)C(OC)OC)cc2c1
Solvent: O
Solvent: CC(C)=O
Product: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(C=O)SCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.3 %

Procedure:
A mixture of N-[2-(benzylthio)-3,3-dimethoxypropyl]-5-(2-methoxyethoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (3.0 g), Amberlyst (registered trade mark) 15 ion exchange resin (600 mg), acetone (80 mL) and water (260 mg) was stirred at room temperature for 15 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (2:3-1:9, volume ratio) to give the title compound (2.09 g, yield 75%) as colorless crystals.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:8][CH:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2].[Br:30]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2[Br:30])[CH2:8][CH:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OCC1CC(n2cnc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Reaction time: 4 h

Procedure:
(±)-(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (1.32 g, 2.98 mmol) in dry N, N-dimethylformamide (6 mL) was heated to 60° C. Portions (ca. 1 mmol each) of N-bromosuccinimide (1.59 g, 8.93 mmol) were added over 5 hours. Heating was continued for an additional 4 hours. Volatiles were removed in vacuo and the residue chromatographed on silica gel. Title compound eluted with 1:1 hexane-ethylacetate as a tan powder (1.1 g, 69%), 1H-NMR identical with recrystallized sample. Such a sample was recrystallized from ethanol-water to a white powder, m.p. 156°-159° C.; 1H-NMR (DMSO-d6)δ: 8.34, 7.97 (both s, 1 each, 2 benzimidazole CH), 5.6 (m, 1, OCH), 5.3 (m, 1, OCH), 5.2-5.0 (m, 1, NCH), 4.4-4.2 (m, 2, OCH2), 2.7-2.5 (m, 1, CH), 2.4-2.0 (m) overlapping 2.1 and 2.07 (both s, total 8, CH2 and 2CH3CO), 1.92 (s, 3, CH3CO); mass spectrum (CI): 527 (6.6), 525 (45), 523 (100), 521 (65, M+1), 257 (48, M-B).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li]CCCC.[CH3:15][C:16]1([CH3:24])[O:21][C:20](=[O:22])[CH:19]=[C:18]([CH3:23])[O:17]1.[F:25][C:26]([F:33])([F:32])[C:27]([O:29]CC)=[O:28].CC(O)=O>C1COCC1>[CH3:15][C:16]1([CH3:24])[O:21][C:20](=[O:22])[CH:19]=[C:18]([CH2:23][C:27]([OH:29])([OH:28])[C:26]([F:33])([F:32])[F:25])[O:17]1
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C=C(CC(O)(O)C(F)(F)F)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a solution of hexamethyldisilazane (167 mL, 800 mmol) in THF (200 mL) at 0° C. was cannulated n-BuLi (500 mL, 800 mmol) and the mixture was stirred at 0° C. for 30 min, then cannulated into a solution of freshly distilled 2,2,6-trimethyl-1,3-dioxin-4-one (56.9 g, 400 mmol) in THF (400 mL) at −78° C., keeping the internal temperature below −60° C. Stirring was continued at −78° C. for 1 h, then a solution of ethyl 2,2,2-trifluoroacetate (52.5 mL, 440 mmol) in THF (100 mL) was added quickly (<1 min; internal temperature remained below −70° C.). The cooling bath was removed and stirring was continued at −78 to 0° C. for 2 h. Cooled to −45° C., then HOAc (57.3 mL, 1000 mmol) was added and the mixture was warmed to −10° C. Poured into ice cold 0.5 M HCl (pH 1), extracted with TBME, washed with sat. NaHCO3-sol., ice cold 0.5 M HCl and brine, dried over Na2SO4. Removal of the solvent in vacuum (bath temperature below 40° C.) left a yellow oil, added THF (ca. 200 mL), toluene (ca. 50 mL) and H2O (ca. 20 mL) and evaporated to dryness to give the title compound as a light yellow solid (89.27 g, 87%). MS (ISN) 237.0 [(M−H)−].
Reaction SMILES: [CH:1]([O:4][CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:3])[CH3:2].[Cl-].[Li+].Cl.[O:29]1CCO[CH2:31][CH2:30]1>>[C:30]([C:14]1[CH:13]=[C:12]([CH2:11][CH:5]([O:4][CH:1]([CH3:3])[CH3:2])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:17]=[CH:16][CH:15]=1)(=[O:29])[CH3:31]
Reactant: C1COCCO1
Reactant: CCOC(=O)C(Cc1cccc(OS(=O)(=O)C(F)(F)F)c1)OC(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Product: CCOC(=O)C(Cc1cccc(C(C)=O)c1)OC(C)C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
2.037 g of Ethyl 2-isopropoxy-3-(3-[(trifluoromethyl)sulfonyl]oxyphenyl)-propanoate, 2.5 g of ethyl [1-(1,1,1-tributylstannyl)vinyl]ether, 500 mg of lithium chloride and 186 mg of dichlorobis(triphenylphosphine) palladium were dissolved in 15 ml of dioxane, and the mixture was stirred at 90° C. overnight under nitrogen atmosphere. The solution was cooled in ice bath, added with 1N-hydrochloric acid, and extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off. The residue was purified by silica gel column chromatography, to give 1.041 g of the title compound in the 6:1 hexane-ethyl acetate fraction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:36])[CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][C:32]([F:34])([F:35])[F:33])[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:36])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(CC(F)(F)F)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: COc1cn(C(CC(F)(F)F)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
21 mg (38 μmol) of ethyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4,4-trifluorobutanoyl}amino)benzoate (racemate) in 0.75 ml of methanol/water (4/1) were reacted with 25 mg (77 μmol) of caesium carbonate according to General Method 4. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 9 mg (46% of theory)
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:26])[O:27][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C(O)CCCCCCCCCCCCCCO
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1CCCCCCCCCCCCCCO1

Procedure:
To a refluxing solution of 510 mg (2.0 mmol) of 2-chloro-1-methylpyridinium iodide in 50 ml of toluene, there was added a solution of 134 mg (0.5 mmol) of 15-hydroxypentadecanoic acid and 404 mg (4.0 mmol) of triethylamine in 40 ml of toluene over a period of 8 hours at a continuous and uniform rate and the reaction mixture was refluxed for and additonal 30 minutes after the addition was completed. After evaporation of the solvent, the residue was separated chromatographically on a silica gel column. 1,15 -pentadecanolide was obtained in 63%. yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl[S:13]([C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:15])=[O:14]>CN(C1C=CN=CC=1)C>[CH3:21][O:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=1[S:13](=[O:14])(=[O:15])[NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 33.9 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.69 mmol), methyl 2-chlorosulfonylbenzoate (160 mg, 0.69 mmol) and DMAP (cat.) gave the title compound (80 mg, 35%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[Cl:7][C:8]1[C:9]([F:39])=[C:10]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:37][CH3:38])=[C:22]([CH2:25][N:26]([CH3:36])[C:27]4([C:33]([NH2:35])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:23]=3)[N:18]=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>ClCCl>[Cl:7][C:8]1[C:9]([F:39])=[C:10]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:37][CH3:38])=[C:22]([CH2:25][N:26]([CH3:36])[C:27]4([C:33]([NH2:35])=[O:34])[CH2:32][CH2:31][N:30]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:29][CH2:28]4)[CH:23]=3)[N:18]=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCNCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
Methanesulfonyl chloride (7.5 μl, 0.094 mmol) was added to a stirred solution of 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-carboxamide hydrochloride (0.05 g, 0.085 mmol) and triethylamine (53 μl, 0.38 mmol) in dichloromethane (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, concentrated and purified by preparative LCMS (standard basic system) to give the title product (0.0107 g, 23%) as a white solid; 1H NMR Spectrum: (DMSO-d6) 1.98 (m, 2H), 2.22 (m, 2H), 2.36 (s, 3H), 2.84 (s, 3H), 2.96 (m, 2H), 3.44 (m, 2H), 3.66 (s, 2H), 3.98 (s, 3H), 7.19 (s, 1H), 7.26-7.30 (m, 3H), 7.52-7.53 (m, 2H), 8.33 (s, 1H), 8.42 (s, 1H), 9.70 (s, 1H); Mass Spectrum: (M+H)+ 551.
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]1[CH2:27][CH2:26][O:25][C:23]1=[O:24])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(OCC)(=O)C.CCCCCC>O1CCCC1.C(OCC)(=O)C.C(O)C>[C:1]([O:20][CH2:21][CH:22]([CH2:27][CH2:26][OH:25])[CH2:23][OH:24])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCCC1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: OCCC(CO)COC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
α-Trityloxymethyl-γ-butyrolactone (60.21 g, 0.168 mol) was added in small portions to a stirred suspension of lithium aluminium hydride (9.53 g, 0.251 mol) in dry tetrahydrofuran (300 ml) and the mixture was refluxed for 1 h. Slow addition of 10 ml H2O+10 ml 15% NaOH and 30 ml H2O) produced a white sandy precipitation which was filtered off and washed with 2×50 ml tetrahydrofuran. The filtrate was evaporated to a small volume and dissolved in diethyl ether (300 ml), silica gel (250 g) was added and the mixture was carefully evaporated to a homogeneous powder. In a chromatography column the crude product--silica gel mixture was placed on top of silica gel (250 g) in n-hexane. Eluting with ethyl acetate+n-hexane (1+3), 2200 ml, removed trityl alcohol. Further eluting with ethyl acetate+ethanol (9+1) gave fractions 2900-3700 ml (from start), which after evaporation in vacuum produced a crystallizing oil. Yield 52.77 g (87%). TLC on silica: ethyl acetate+n-hexane (1+3), Rf 0.05; ethyl acetate+ethanol (9+1), Rf 0.81.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].F[C:6]1[C:11]2[C:12](=[O:21])[C:13]3[CH:14]=[CH:15][N:16]=[CH:17][C:18]=3[C:19](=[O:20])[C:10]=2[C:9](F)=[CH:8][CH:7]=1>C1COCC1>[NH2:3][CH2:2][CH2:1][NH:4][C:6]1[C:11]2[C:12](=[O:21])[C:13]3[CH:14]=[CH:15][N:16]=[CH:17][C:18]=3[C:19](=[O:20])[C:10]=2[C:9]([NH:3][CH2:2][CH2:1][NH2:4])=[CH:8][CH:7]=1
Reactant: O=C1c2ccncc2C(=O)c2c(F)ccc(F)c21
Reactant: NCCN
Solvent: C1CCOC1
Product: NCCNc1ccc(NCCN)c2c1C(=O)c1ccncc1C2=O
Reaction time: 3 h

Procedure:
To a warm solution (55° C.) of ethylenediamine (154.4 mL, 2.29 mol) in THF (1400 mL), 6,9-difluorobenzo[g]isoquinoline-5,10-dione (70.1 g, 0.29 mol) was portionwise added over a period of 2.5 hours (about 4.6 g/10' each portion). The mixture was stirred for 3 hours at the same temperature and a blue precipitate was gradually formed. After one night stirring at 25° C., the suspension was filtered under nitrogen blanket, washed with THF (200 mL) and dried under vacuum (15 torr, 60° C., 3 h) to yield crude 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione as dihydrofluoride salt (117 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C.CCOCC>[CH:20]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12])([CH3:22])[CH3:21]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(C)c1
Temperature: 60 °C
Yield: 89.9 %

Procedure:
To methyl 4-hydroxy-3-methyl-benzoate (1.0 g, 59.8 mmol) in dry DMF (62 mL) was added finely ground potassium carbonate (33.1 g, 239.3 mmol) followed by 2-iodopropane (20.3 g, 12.0 mL, 119.6 mmol). The reaction mixture was heated at 60° C. for 2 hours. The reaction mixture was cooled and diluted with ether (350 mL), and filtered over celite. The filtrate was washed with water (3×100 mL) and brine (100 mL) solution. The layers were separated and organics were dried over MgSO4. The solvent was evaporated and resulting residue was purified by silica gel using 0-30% EtOAc/hexanes mixtures as eluent to give methyl 4-isopropoxy-3-methylbenzoate as a colorless oil (11.2 g, 89%). ESI-MS m/z calc. 208.25. found 209.2 (M+1)+; Retention time: 1.93 minutes (3 min run). Lithium hydroxide (4.4 g, 181.6 mmol) was added to a solution of methyl 4-isopropoxy-3-methylbenzoate (11.2 g, 53.8 mmol) in tetrahydrofuran (31 mL) and water (31 mL). The mixture was rapidly stirred and heated at 65° C. for 6 hours. The reaction mixture was cooled, diluted with water (75 mL) and extracted with ether (2×50 mL). The aqueous layer was acidified to pH 2 with 6N aq. HCl and extracted with ethyl acetate (4×75 mL). The combined organics were washed with water (75 mL) and brine solution (75 mL) and layers were separated. The organics were dried over MgSO4 and concentrated in vacuo to give 4-isopropoxy-3-methyl-benzoic acid (9.5 g, 82%) as colorless crystals. ESI-MS m/z calc. 194.2. found 195.3 (M+1)+; Retention time: 1.53 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.78-7.71 (m, 2H), 7.02 (d, J=8.6 Hz, 1H), 4.70 (dt, J=12.1, 6.0 Hz, 1H), 2.15 (s, 3H), 1.30 (d, J=6.0 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]([O:6][C@@H:7]([CH2:25][CH3:26])[C@H:8]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.C([O:37][B:38](OC(C)C)[O:39]C(C)C)(C)C>O1CCCC1>[Si:18]([O:17][C@H:8]([CH2:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[C@H:7]([CH2:25][CH3:26])[O:6][C:5]1[CH:27]=[CH:28][C:2]([B:38]([OH:39])[OH:37])=[CH:3][CH:4]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC[C@H](Oc1ccc(Br)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C

Procedure:
Prepared according to the method as described in Example 5b) from (3R,4S)-3-[4-(4-bromophenoxy)-3-(t-butyldimethylsilanyloxy)hexyl]pyridine (0.71 g, Example 88a)), tertbutyl lithium (1.80 ml, 1.7M in hexanes) and tri-isopropylborate (0.74 ml) in dry tetrahydrofuran (25 ml). After work up, the residue was purified by column chromatography eluting with a gradient 0-25% ethanol in ethyl acetate to give the sub-title compound as a foam (0.41 g).