Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]([NH:18][S:19]([C:22]1[C:23]([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[C:30]([F:43])[CH:29]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([NH:18][S:19]([C:22]1[C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:2]3[CH:3]=[C:4]4[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=3)[NH:7][CH:6]=[CH:5]4)=[C:30]([F:43])[CH:29]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=[N+]([O-])c1cc(Br)cc2cc[nH]c12
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cc([N+](=O)[O-])c3[nH]ccc3c2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 88 using 5-bromo-7-nitroindole and N-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide. 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 8.27-8.18 (m, 2H), 7.65-7.58 (m, 2H), 7.58-7.50 (m, 1H), 7.50-7.35 (m, 4H), 6.83-6.77 (m, 1H), 1.17-1.03 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH3:31])=[CH:25]2.[I-].[K+].Cl.Cl[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(=O)([O-])O.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH3:31])=[CH:25]2
Reactant: ClCCN1CCOCC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CO
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCN(CCN2CCOCC2)CC1
Reaction time: 1 h
Yield: 122.8 %

Procedure:
To a solution of 6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (500 mg, 1.2 mmol), (prepared as described in example 70), in methanol (11.5 ml) containing potassium iodide (99 mg, 0.6 mmol) was added 4-(2chloroethyl)morpholine hydrochloride (134 mg, 0.72 mmol) followed by sodium hydrogen carbonate (151 mg, 1.8 mmol). After stirring for 1 hour at reflux, 4-(2-chloroethyl)morpholine hydrochloride (134 mg, 0.72 mmol) and sodium hydrogen carbonate (151 mg, 1.8 mmol) were added. After stirring 1 hour at reflux, the mixture was cooled and the precipitate was filtered, washed with methanol followed by water and dried over phosphorus pentoxide to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-(2-morpholinoethyl)piperidin-4-ylmethoxy)quinazoline (470 mg, 73%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH2:7][CH2:8][C:9]1([OH:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Cl:1][CH2:2][C:3]([NH:6][CH2:7][CH2:8][C:9]1([OH:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][CH2:10]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CCN)CC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(CCNC(=O)CCl)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Chloroacetyl chloride (0.483 mL) was added dropwise over 10 minutes to a vigorously stirred mixture at 0° C. of tert-butyl 4-(2-aminoethyl)-4-hydroxypiperidine-1-carboxylate (example 89, step b) (1.1 g) in ethyl acetate (25 mL) and potassium carbonate (1.77 g) dissolved in water (20 mL). The mixture was then stirred at 0° C. for 45 minutes before being extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography eluting with ethyl acetate. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.9 g.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]4[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=4)[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:27][C:25]1[CH:24]=[C:23]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=2)[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.8 %

Procedure:
To a cooled and stirred solution of 3′-[4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.24 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.081 g, 34%). MS (ISP) 471.2 [(M+H)+]; mp 220° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14](Cl)=[O:15])[CH:7]=[CH:6]2.[NH3:18]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14]([NH2:18])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C(C)C(=O)Cl)ccc2c1
Reactant: N
Solvent: Cc1ccccc1
Product: COc1ccc2cc(C(C)C(N)=O)ccc2c1
Reaction time: 3 h

Procedure:
Into 300 ml of dry toluene, were dissolved 10.8 g of oa (6-methoxy-2-naphthyl)-propanoic acid chloride, followed by introducing dry ammonia at a temperature not more than 15° C. for 30 minutes. Stirring was continued at room temperature for 3 hours, and then precipitated while solid was filtered off. The resulting white solid was washed with toluene and then water, followed by recrystallizing with ethanol to obtain 10.0 g of oa (6-methoxy-2-naphthyl)-propanamide.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:24]([O-:26])=[O:25])[NH:21][CH2:20][CH2:19][CH2:18][S:17][C:16]2([CH3:23])[CH3:22])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:24]([OH:26])=[O:25])[NH:21][CH2:20][CH2:19][CH2:18][S:17][C:16]2([CH3:22])[CH3:23])(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)[O-])NCCCSC2(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)NCCCSC2(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-2,2-dimethyl-1,4-thiazepane-3-carboxylate (220 mg, 0.49 mmol) in methylene chloride (4 mL) was added trifluoroacetic acid (1.5 mL) and the mixture was stirred for 2 h at room temperature. The solvent was removed in vacuo. Traces of trifluoroacetic acid was removed by adding toluene (1 mL) and removing the solvent to obtain 170 mg (88%) of (3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-2,2dimethyl-1,4-thiazepane-3-carboxylic acid; 1H NMR (300 MHz, CDCl3) δ 1.42 (s, 3H), 1.60 (s, 3H), 1.85 (m, 3H), 1.91 (m, 1H), 2.17 (m, 1H), 2.67 (m, 1H), 2.82 (m, 1H), 3.54 (m, 1H), 3.82 (m, 1H), 4.59 (s, 1H), 4.68 (m, 2H), 7.0 (d, 2H, J=8.7 Hz), 7.75 (d, 2H, J=8.7 Hz); HRMS (C18H23NO5S2)(M+); cald. 397.1018, found 397.0998.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=1.C([N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1)(=O)C>C(#N)C.[OH-].[Na+]>[CH3:26][C:24]1[N:23]([CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[N:4]=2)[CH:22]=[N:21][CH:25]=1
Reactant: ClCc1nc2ccccc2n1-c1ccccc1
Reactant: CC(=O)n1cnc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1cncn1Cc1nc2ccccc2n1-c1ccccc1
Yield: 11.7 %

Procedure:
A mixture of 2-chloromethyl-1-phenyl-1H-benzimidazole (4.8 g) and 1-acetyl-4-methylimidazole (2.4 g) in acetonitrile (25 ml) was refluxed for 48 hours. After removal of the solvent, the residue was pulverized in diethyl ether to give powder, which was taken up in 2.5 N sodium hydroxide (20 ml) and refluxed for 15 minutes. The resultant mixture was extracted twice with chloroform. The combined organic layer was extracted twice with 1 N hydrochloric acid. The combined aqueous layer was adjusted to pH 8.0 with aqueous sodium bicarbonate and extracted twice with chloroform. The combined extract was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The resultant residue was subjected to column chromatogeaphy on silica gel (60 g) eluting with a mixture of chloroform and methanol (50:1) to give an oily product. The oily product was triturated twice in diethyl ether and then in the mixture of diethyl ether and isopropyl alcohol (2:1) to give powder of 2-(5-methylimidazol-1-yl)methyl-1-phenyl- 1H-benzimidazole (0.65 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[NH:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]([NH2:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:5][CH2:4][CH2:3][CH2:2][N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]([NH2:13])=[O:12]
Reactant: OCCCBr
Reactant: NC(=O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)[C@@H]1CCCN1CCCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.6 %

Procedure:
3-Bromo-1-propanol (584 mg, 4.2mmol) was added to a mixture of (S)-pyrrolidine-2-carboxamide (399 mg, 3.5 mmol) and potassium carbonate (966 mg, 7 mmol) in acetonitrile (10 ml). The mixture was heated at reflux for 5 hours and the mixture was stirred for 18 hours at ambient temperature. The insolubles were removed by filtration and the solvent was removed from the filtrate by evaporation The residue was purified by column chromatography on silica eluting with methylene chloride/methanol (9/1 followed by 8/2) to give (S)-1-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (365 mg, 60%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1([C:14]([OH:16])=O)[CH2:13][CH2:12]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[Br-:29].[Br-].[NH3+:31][CH2:32][CH2:33][CH2:34][P+:35]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C=O.C(Cl)Cl>[Br-:29].[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1([C:14]([NH:31][CH2:32][CH2:33][CH2:34][P+:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:16])[CH2:12][CH2:13]1)[CH3:9])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CC1(C(=O)O)CC1)C(=O)OC(C)(C)C
Reactant: [NH3+]CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Br-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(CC1(C(=O)NCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
1-{[(tert-butoxycarbonyl)(methyl)amino]methyl}cyclopropanecarboxylic acid (680 mg, 3.0 mmol) was dissolved in N,N-dimethylformamide (6.8 mL) and treated with N,N-carbonyldiimidazole (571 mg, 3.52 mmol). The mixture was stirred at room temperature for 30 minutes. To the solution was added (3-ammoniopropyl)(triphenyl)phosphonium dibromide (1.93 g, 4.00 mmol). The mixture was stirred overnight at room temperature and then diluted with methylene chloride and washed with 5% aqueous lithium chloride (3 times), 1N aqueous hydrogen chloride, and saturated sodium bicarbonate. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude title compound. The crude product was purified on a silica gel column eluting with a gradient of 0-20% methanol with methylene chloride to isolate the title compound (810 mg, 40%, 91% pure).
Reaction SMILES: [I-:1].[OH:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1.CO.C(=O)([O-])[O-].[K+].[K+].[CH2:30]([N:32]([CH3:36])[C:33](Cl)=[O:34])[CH3:31]>C(O)CO>[I-:1].[CH2:30]([N:32]([CH3:36])[C:33]([O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1)=[O:34])[CH3:31]
Reactant: CCN(C)C(=O)Cl
Reactant: C[C@@H](c1ccccc1)[N+](C)(C)[C@@H](C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: OCCO
Solvent: CO
Product: CCN(C)C(=O)Oc1cccc([C@H](C)[N+](C)(C)[C@@H](C)c2ccccc2)c1
Temperature: 60 °C

Procedure:
Mix 7.9 g (0.02 mol) of (S)-1-(3-hydroxyphenyl)-N,N-dimethyl-N—((S)-1-phenylethyl)ethanaminium iodide (formula VIII) with 100 ml of methanol, 4.1 g (0.03 mol) of potassium carbonate, 3.6 g (0.03 mol) ethyl(methyl)carbamic chloride and 0.1 g of macrogol 400 at room temperature, heat it to 60° C. and react it for 12 hours. After it is cooled to room temperature, filter it and reduce the pressure to recover the solvent and receive 9.0 g of red-brown liquid to be directly used in the next reaction.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:11][CH2:12][CH3:13])[O:8][C:9]=1[Br:10])=O.CC(C[AlH]CC(C)C)C.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(Cl)Cl>[Br:10][C:9]1[O:8][C:7]([CH2:11][CH2:12][CH3:13])=[N:6][C:5]=1[CH2:3][OH:2]
Reactant: CCCc1nc(C(=O)OC)c(Br)o1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CCCc1nc(CO)c(Br)o1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
A 4.245 g (17.12 mmol) sample of the compound from step 29a above was dissolved in 80 mL of methylene chloride and cooled to 0° C. DIBAL-H (1.0M in hexane, 37.0 mmol) was added via syringe. The resulting solution was stirred for 15 min. Methanol (2 mL) was added slowly, followed by 80 mL of satd. potassium sodium tartrate, and the mixture was stirred for 1 hour. The organic layer was separated, and the aqueous layer was extracted with 2×50 mL of methylene chloride. The organics were combined, dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica gel, eluting with 20-60% ethyl acetate in hexane, to afford 3.490 g (93% yield) of the title product. MS:220(M+H)+, 222(M+H)+, 237(M+NH4)+, 239 (M+NH4)+. NMR (CDCl3) δ:4.50 (s, 2H), 2.72 (t, J=8 Hz, 2H), 2.0 (br s, 1H), 1.79 (sx, J=8 Hz, 2H), 1.00 (t, J=8 Hz, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH3:17][O:16][C:12]1[C:11]2[C:7]([C:34]3[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=3)=[N:8][N:9]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:10]=2[CH:15]=[CH:14][N:13]=1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCOCC1

Procedure:
A solution of 4-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (150 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (167 mg), tetrakis(triphenylphosphine)palladium(0) (45.5 mg) and 2M aqueous sodium carbonate solution (1.0 mL) in DME (15 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (119 m).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][O:14][C:15]3[CH:30]=[CH:29][C:18]([CH2:19][CH:20]([C:25]([O:27]C)=[O:26])[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:24][O:23][C:21]([CH:20]([CH2:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][O:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)=[CH:30][CH:29]=1)[C:25]([OH:27])=[O:26])=[O:22]
Reactant: COC(=O)C(Cc1ccc(OCCOc2ccc3ncccc3c2)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3ncccc3c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
To a solution of dimethyl 4-[2-(6-quinolinoxy)ethoxy]benzylmalonate (0.44 g, 1.07 mmol) in a mixture of methanol (4.3 ml) and tetrahydrofuran (2.1 ml) at 0° C. is added a 2 mol/L aqueous solution of sodium hydroxide (0.59 ml, 1.18 mmol). The mixture is stirred for 2 h at room temperature, and then the solvent is removed under a vacuum. The residue was dissolved in saturated aqueous sodium bicarbonate (10 ml) and washed with ethyl acetate (10 ml). The aqueous solution is acidified to pH 2–3 with dilute hydrochloric acid and extracted with ethyl acetate (3×15 ml). The combined extracts are washed with water (20 ml) and brine (20 ml), dried over sodium sulfate, and concentrated. The residue is crystallized from ethyl acetate to give the title compound (0.23 g, 54%). HRMS calcd for C22H25NO6: 399.4402. Found: 399.4405. MA calcd for C22H25NO6: C, 66.15%; H, 6.31%; N, 3.51%. Found: C, 66.32%; H, 6.34%; N, 3.48%.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([F:27])[CH:15]=[CH:16][C:17]=2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:12]=1.CS(O[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=1)(=O)=O>CN(C)C=O>[F:27][C:14]1[CH:15]=[CH:16][C:17]([N:21]2[CH2:26][CH2:25][N:24]([CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=3)[CH2:23][CH2:22]2)=[C:18]2[C:13]=1[N:12]=[C:11]([CH3:10])[CH:20]=[CH:19]2
Reactant: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc2c(N3CCNCC3)ccc(F)c2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)ccc(F)c2n1
Temperature: 100 °C
Yield: 46 %

Procedure:
N,N-Diisopropylethylamine (0.25 mL; 3 eq) was added to a solution of 2-methyl-5-(1-piperazinyl)-8-fluoro quinoline (0.170 g; 1 eq) and 2-(3-nitrophenyl)ethyl methanesulfonate (D4) (0.17 g; 1 eq) in dimethylformamide (4.0 mL). The reaction mixture was heated to 100° C. for 10 hours. The dark solution was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (3 mL) and brine (1 mL) and extracted into ethyl acetate (3×3 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel, eluting with a gradient from dichloromethane to dichloromethane-methanol (98:2) affording the title compound in 46% yield (0.126 g).
Reaction SMILES: C(OC(=O)[N:7]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:8]1[S:9][C:10]([CH:14](O)[C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([Si](C(C)C)(C(C)C)C(C)C)[CH:16]=2)=[C:11]([Cl:13])[N:12]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>C(#N)C>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][NH:7][C:8]2[S:9][C:10]([CH2:14][C:15]3[C:23]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)=[C:11]([Cl:13])[N:12]=2)=[CH:37][CH:38]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2sc(N(Cc3ccc(Cl)cc3)C(=O)OC(C)(C)C)nc2Cl)c2cccnc21
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CNc2nc(Cl)c(Cc3c[nH]c4ncccc34)s2)cc1
Yield: 13.1 %

Procedure:
A mixture of (4-Chloro-benzyl)-{4-chloro-5-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-thiazol-2-yl}-carbamic acid tert-butyl ester (97, 76 mg, 0.11 mmol), triethylsilane (0.5 mL, 3 mmol), and trifluoroacetic acid (0.25 mL, 3.2 mmol) in acetonitrile (5 mL) was refluxed for 3 hours. The reaction mixture was poured into iced water, extracted with ethyl acetate, washed with sodium bicarbonate, brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a yellow solid (P-0083, 5.6 mg, 14%). MS (ESI) [M+H+]=389.35, 390.36.
Reaction SMILES: [OH:1][C@H:2]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:29]=1)[CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:21]([CH2:22][C:23]([O:25]CC)=[O:24])[N:20]=[N:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>>[OH:1][C@H:2]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([NH:35][S:36]([CH3:39])(=[O:37])=[O:38])[CH:29]=1)[CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:21]([CH2:22][C:23]([OH:25])=[O:24])[N:20]=[N:19][N:18]=3)=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)Cn1nnnc1-c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(-c4nnnn4CC(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from ethyl [5-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}phenyl)-1H-tetraazol-1-yl]acetate (which was obtained in Example 98) by NaOH hydrolysis as an off -white solid; mp >210° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.30-1.50 (m, 2H), 1.80-2.00 (m, 2H), 2.60-3.50 (m, 5H), 2.92 (s, 3H), 3.70-3.85 (m, 2H), 4.50-4.60 (m, 1H), 4.70-4.80 (m, 2H), 6.84 (d, J=8.2 Hz, 1H), 6.95-7.05 (m, 3H), 7.20 (d,,J=1.6 Hz, 1H), 7.66 (d, J=8.7 Hz, 2H); MS (ES) m/z: 530.2 (M−H)−; HRMS Calcd. for C21H28N7O4S(M-H)−: 530.1827. Found: 530.1827.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]#[N:23])[CH2:18][CH2:17]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](=[N:27][OH:28])(N)[CH3:25]>CCOC(C)=O.C1COCC1.O.[Cl-].[Zn+2].[Cl-]>[CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[O:28][N:27]=[C:24]([CH3:25])[N:23]=3)[CH2:18][CH2:17]2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Cc2ccccc2)nc(NC2CCN(C#N)CC2)n1
Reactant: CC(N)=NO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccccc2)nc(NC2CCN(c3nc(C)no3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4-benzyl-6-methyl-pyrimidin-2-ylamino)-piperidine-1-carbonitrile (135 mg, 0.44 mmol) and acetamidoxime (39 mg, 0.53 mmol) in EtOAc (1 mL) and THF (1 mL) was added within 10 minutes a solution of zinc chloride (73 mg, 0.53 mmol) in EtOAc (1 mL). After stirring at room temperature for 4 hours the reaction was heated to reflux over night under nitrogen. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH2Cl2/MeOH 19:1 (v/v) as eluent. The title compound was obtained as a colorless gum (98 mg, 61%).