Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][N:7]([C:9]3[N:14]=[CH:13][C:12]([NH:15][CH:16]([C:20]4[CH:35]=[CH:34][C:23]([C:24]([NH:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:25])=[CH:22][CH:21]=4)[CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1.O1CCCC1.[OH-].[Li+].FC(F)(F)C(O)=O>CO.O.C(#N)C>[CH:1]1([C:4]2[CH:5]=[N:6][N:7]([C:9]3[N:14]=[CH:13][C:12]([NH:15][CH:16]([C:20]4[CH:21]=[CH:22][C:23]([C:24]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[CH:34][CH:35]=4)[CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCCC(Nc1ccc(-n2cc(C3CC3)cn2)nc1)c1ccc(C(=O)NCCC(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: CCCC(Nc1ccc(-n2cc(C3CC3)cn2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of crude (+/−)-ethyl N-[4-(1-[{6-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl]amino}butyl)benzoyl]-beta-alaninate (63 mg, 0.13 mmol) was dissolved in methanol (0.26 ml) and tetrahydrofuran (0.13 ml) and treated with aqueous 2.0M lithium hydroxide (0.13 ml, 0.26 mmol). The mixture was stirred at ambient temperature for 12 hours. The reaction was concentrated in vacuo. The residue was acidified with aqueous 1.0M hydrochloric acid and concentrated in vacuo a second time. Purification by reversed-phase HPLC on a Waters Sunfire C18 19×100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave the product. Analytical LCMS: retention time 2.94 minutes (Atlantis C18 4.6×50 mm, 5 μM column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 448.2.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([OH:26])[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.[CH2:31](O)[CH2:32][CH3:33].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>C1COCC1>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([O:26][CH2:31][CH2:32][CH3:33])[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1
Reactant: CCCO
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(O)c21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCOc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1C(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, 80 mg (0.20 mmol) of the compound from example 109, 13 mg (16 μl, 0.22 mmol) of n-propanol and 57 mg (0.22 mmol) of triphenyl phosphine were suspended in 0.8 ml THF, mixed for 10 min in the ultrasonic bath and finally 44 mg (43 μl, 0.22 mmol) of diisopropyl azodicarboxylate was added and it was stirred for 1 h at RT. The reaction mixture was purified by preparative HPLC (Reprosil C18, gradient of acetonitrile/0.01% aq. formic acid). Yield: 48 mg (55% of theor.)
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].CC([O-])(C)C.[K+].F[C:12]1[CH:17]=[CH:16][C:15]([I:18])=[C:14]([CH3:19])[CH:13]=1>CN(C=O)C>[I:18][C:15]1[CH:16]=[CH:17][C:12]([O:4][CH2:1][CH2:2][CH3:3])=[CH:13][C:14]=1[CH3:19]
Reactant: Cc1cc(F)ccc1I
Reactant: CCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(I)c(C)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
3.44 mL (45.8 mmol) 1-propanol is added to an ice cold mixture of 3.42 g (30.5 mmol) KOtBu in 18 mL DMF. After stirring the mixture for 10 min 1.80 g (7.63 mmol) 4-fluoro-1-iodo-2-methylbenzene are added and the reaction mixture is stirred at 80° C. for 3 h. The reaction is quenched by the addition of a sat. aq. NH4Cl solution and extracted with EtOAc (2×). The combined organic layers are washed with sat. aq. NH4Cl solution and brine, dried with Na2SO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, heptane/EtOAc 9/1).
Reaction SMILES: [C:1]1([CH3:39])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:18][CH2:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14][N:13]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[BrH:40].C(O)(=O)C>>[BrH:40].[C:1]1([CH3:39])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][N:13]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)(=[O:30])=[O:31])[CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N2CCNCCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1

Procedure:
From N,N′,N″-tris(p-toluenesulfonyl)-1,4,7-triazacyclononane (1.3.13.31 and HBr/acetic acid as the hydrobromide salt.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:9]1[C:22]([OH:24])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[C:27]([F:36])=[C:28]([C:32]2([NH2:35])[CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17])[C@H:9]1[C:22](=[O:24])[NH:35][C:32]1([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[C:27]=2[F:36])[CH2:33][CH2:34]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: NC1(c2cccc(Cl)c2F)CC1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](F)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)NC1(c2cccc(Cl)c2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,3S,4S)-3-(tert-butyl-dimethyl-silanyloxy)-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (300 mg, 0.825 mmol), 1-(3-chloro-2-fluoro-phenyl)-cyclopropylamine (prepared as described in Part C, 272 mg, 0.908 mmol) and HBTU (376 mg, 0.99 mmol) in DMF (10 mL) was added DIPEA (0.432 ml, 2.476 mmol) under nitrogen atmosphere. The reaction mixture was stirred 2 h at 25° C. Then quenched by addition of a saturated aqueous solution of NaHCO3 and extracted with EtOAc (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1). MS (UPLC): 531.5/533.5 [M+H]+, 505.5 [M+NH4]+, 510.4 [M+Na]+; tR (UPLC conditions m): 1.55 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][C:6]([CH:12]=[O:13])=[CH:5]2.I[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][C:6]([CH:12]=[O:13])=[CH:5]2)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=CC1=Cc2cc(O)ccc2OC1
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCOc1ccc2c(c1)C=C(C=O)CO2
Reaction time: 1 h

Procedure:
2 g (11.4 mmol) of the hydroxyaldehyde obtained in Step A and also 2.7 g (13.6 mmol) of iodopentane are added to a suspension of 1.9 g (13.6 mmol) of potassium carbonate in 50 ml of anhydrous acetone; the medium is then heated at reflux. After one hour, 1.2 g of potassium carbonate are added to the solution, and that operation is then re-started after one hour. At the end of 12 hours of heating at reflux, the solution is allowed to cool, the salts are filtered off over Celite and the solvent is then evaporated in vacuo. Chromatography on a silica column (eluant:petroleum ether/ethyl acetate 90/10) yields the title aldehyde in the form of a yellow syrup.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:29]1([CH2:35][C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:40]([C:39]3[CH:38]=[CH:37][C:36]([CH2:35][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:43][CH:42]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccc(Cl)cc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: Clc1ccc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(CN6CCOCC6)cc5)nc34)CC2)cc1
Temperature: 70 °C
Reaction time: 9 h

Procedure:
To a mixture of 5-bromo-4-[4-(4-chloro-benzyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.064 g, 0.15 mmol) and EtOH (6.5 ml) was added 4-morpholin-4-ylmethyl-benzaldehyde (0.038 g, 0.18 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.60 ml, 0.60 mmol). The reaction mixture was stirred at 70° C. for 9 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column and elution with a gradient of methanol (0 to 9%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.003 g, 3%). 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.59 (t, J=4.5 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.61 (br s, 4H, piperazine N(CH2)2), 3.66 (br s, 4H, piperazine N(CH2)2), 3.54 (s, 2H) and 3.57 (s, 2H) (NCH2—C6H4Cl and C6H4CH2), 7.41 (m, 4H, C6H4Cl), 7.47 (d, J=8.2 Hz, 2H) and 8.14 (d, J=8.2 Hz, 2H) (3,5-C6H4 and 2,6-C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][C:9](=O)[NH:10]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(-c3ccccc3)cc(=O)[nH]c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(-c3ccccc3)ccnc2c1
Temperature: 0 °C

Procedure:
To a solution of 7-methoxy-4-phenyl-2-quinolinone (4.1 g) in THF (300 mL) at reflux was added lithium aluminum hydride (1M in THF; 65 mL). The mixture was refluxed for 50 hr, cooled to 0° C. and then treated successively with H2O (2.5 mL), 15% aq. NaOH (2.5 mL) and H2O (7.5 mL). The precipitate that formed was removed by filtration, washed with THF, and the filtrate was concentrated and redissolved in acetonitrile (100 mL). To this solution at r.t. was added dropwise a solution of ceric ammonium nitrate (7.7 g) in H2O (30 mL). After the addition was complete, H2O (600 mL) was added and the resulting mixture extracted with EtOAc (3×). The combined organics were washed with H2O (2×) and brine, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; EtOAc/hexane (1:1)) provided the title compound as a beige gum.
Reaction SMILES: CCN(C(C)C)C(C)C.[Si:10]([N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].Cl[CH2:24][C:25]([N:27]([C:30]1[C:31]([Cl:41])=[N:32][N:33]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:34]=1)[CH2:28][CH3:29])=[O:26]>C1COCC1>[Si:10]([N:17]1[CH2:21][CH2:20][CH:19]([CH2:24][C:25]([N:27]([C:30]2[C:31]([Cl:41])=[N:32][N:33]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[CH:34]=2)[CH2:28][CH3:29])=[O:26])[C:18]1=[O:22])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)N1CCCC1=O
Reactant: CCN(C(=O)CCl)c1cn(-c2cccnc2)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(C(=O)CC1CCN([Si](C)(C)C(C)(C)C)C1=O)c1cn(-c2cccnc2)nc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
DIPEA (0.629 mL, 4.41 mmol) was dissolved in THF (20 mL) and cooled to about −78° C. n-Butylithium (1.77 mL, 4.41 mmol) was then added, and the reaction mixture was warmed to about 0° C. for 10 minutes, then re-cooled to about −78° C. Then, 1-(tert-butyldimethylsilyl)pyrrolidin-2-one (0.800 g, 4.01 mmol) was added, and the reaction mixture was warmed to 23° C. and stirred for 1 hour. The reaction was then re -chilled to −78° C., and 2-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (0.600 g, 2.01 mmol) was then added dropwise as a solution in THF (3 mL). The reaction mixture was stirred cold for 30 minutes, then was allowed to slowly warm to room temperature. After 1 hour, the reaction was quenched with a NH4Cl solution and extracted with diethyl ether. The organics were washed with brine, dried over Na2SO4, and concentrated. The resulting oil was purified by flash column chromatography using 0-40% acetone/hexanes as eluent provided the intermediate 2-(1-(tert -butyldimethylsilyl)-2-oxopyrrolidin-3-yl)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (0.604 g, 1.31 mmol). 1H NMR analysis indicated a mixture of molecules present favoring the desired product of about 5:1 over main byproduct. The mixture carried through to the deprotection step without further purification. 2-(1-(tert-Butyldimethylsilyl)-2-oxopyrrolidin-3-yl)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (0.604 g, 1.31 mmol) was dissolved in THF (13 mL) and added was tetrabutylammonium fluoride (TBAF, 1.96 mL, 1.96 mmol). The reaction mixture was stirred for 30 minutes. The reaction product was concentrated onto CELITE® and purified by flash column chromatography using 40-100% acetone/hexanes as eluent providing the title compound (0.204 g, 30% over 2 steps).
Reaction SMILES: Cl[P:2]1[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1.[C:10]1([C:16]2[C:21]([OH:22])=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=[C:18]([CH3:27])[CH:17]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1.C(N(CC)CC)C>C1(C)C=C(C)C=C(C)C=1>[C:10]1([C:16]2[C:21]([O:22][P:2]3[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]3)=[C:20]([C:23]([CH3:25])([CH3:24])[CH3:26])[CH:19]=[C:18]([CH3:27])[CH:17]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1
Reactant: Cc1cc(C2=CCCCC2)c(O)c(C(C)(C)C)c1
Reactant: CC1(C)COP(Cl)OC1
Solvent: Cc1cc(C)cc(C)c1
Solvent: CCN(CC)CC
Product: Cc1cc(C2=CCCCC2)c(OP2OCC(C)(C)CO2)c(C(C)(C)C)c1
Yield: 57.1 %

Procedure:
4.85 g (29.0 mmol) of 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane are added dropwise over a period of about 15 minutes to a solution of 6.6 g (27.0 mmol) of 6-(cyclohexen-1-yl)-2-tert-butyl-4-methylphenol (compound(102), Example 1)and 4.0 ml (29.0 mmol) of triethylamine in 25 ml of mesitylene (1,3,5-trimethylbenzene). The reaction mixture is then refluxed for 18 hours, cooled, filtered, and the filtrate is concentrated on a vacuum rotary evaporator. Crystallization of the residue from dry acetonitrile gives 5.8 g (57%)of 2-[6-(cyclohexen-1-yl)-2-tert-butyl-4-methyl-phenoxy]-5, 5-dimethyl-1,3,2-dioxaphosphorinane, m.p. 97°-102° C. (compound(201), Table 2).
Reaction SMILES: CC([O-])(C)C.[K+].Br[CH2:8][CH2:9][CH2:10][OH:11].[N+:12]([C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[OH:11][CH2:10][CH2:9][CH2:8][N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:23]=2)[CH:19]=[CH:20]1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: OCCCBr
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2ccn(CCCO)c2c1
Temperature: 80 °C

Procedure:
0.13 mol of potassium tert-butylate and 0.13 mol of 3-bromopropanol are added to a solution of 0.11 mol of 6-nitroindole in 400 ml of dimethylformamide. The reaction mixture is heated at 80° C. for 3 hours. After cooling, 300 ml of a 10% potassium carbonate solution are added, and the mixture is diluted with ethyl acetate. After decanting, the aqueous phase is extracted with dichloromethane, and the combined organic phases are then concentrated and purified by chromatography on silica gel to yield the expected product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH2:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([F:8])[CH:7]=1.CON(C)C(=O)CCC(C)(C)C(OC)=O.[CH3:35][C:36]([S@@:39]([NH2:41])=[O:40])([CH3:38])[CH3:37]>C1COCC1.[Cl-].[Na+].O.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[C:36]([S:39](/[N:41]=[C:9](/[C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)\[CH2:10][CH2:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[O:40])([CH3:38])([CH3:37])[CH3:35]
Reactant: COC(=O)C(C)(C)CCC(=O)c1cc(F)cc(F)c1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: COC(=O)C(C)(C)CCC(=O)N(C)OC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CC/C(=N\S(=O)C(C)(C)C)c1cc(F)cc(F)c1
Temperature: 25 °C

Procedure:
To a solution of methyl 5-(3,5-difluorophenyl)-2,2-dimethyl-5-oxopentanoate from Intermediate 1, Step D (500 mg of 85% purity, 1.85 mmol) and (S)-2-methylpropane-2-sulfinamide (336 mg, 2.78 mmol) in THF (9.5 mL), was added titanium tetraethoxide (904 mg, 3.70 mmol). The reaction vessel was quickly sealed and placed into a 60° C. bath for 2 hours. After cooling to ambient temperature the reaction mixture was then diluted with saturated brine (9.5 mL) while experiencing rapid stirring. The resultant slurry was filtered through celite, washing with EtOAc, as needed. The combined organics were then washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography, eluting with a gradient of MeOH:CH2Cl2-0.5:99.5 to 3:97, to give the title compound. MS: m/z=374 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[N:8][N:7]([CH3:14])[N:6]=1)=[O:4].[OH-].[K+]>C1COCC1>[CH3:14][N:7]1[N:6]=[C:5]([C:3]([OH:4])=[O:2])[C:9]([C:10]([F:13])([F:11])[F:12])=[N:8]1
Reactant: COC(=O)c1nn(C)nc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nc(C(=O)O)c(C(F)(F)F)n1
Reaction time: 20 h

Procedure:
A solution of 2-methyl-5-trifluoromethyl-2H-1,2,3-triazole-4-carboxylic acid methyl ester [Compound Number 1.15] (2.09 g; 0.01 mol) and KOH (86%; 0.783 g; 1.2 eq.) in THF (50 ml) was heated at reflux temperature for 3.5 hours. The solution was evaporated, the residue was dissolved in water and acidified to pH 1-2 with HCl (1M). Evaporation of the aqueous solution followed by continuous extration in ethylacetate for 20 hours gave of Compound No 1.13 (2.11 g; 100%) as a crystalline solid.
Reaction SMILES: [CH3:1][Sn:2]([CH3:9])([CH3:8])[C:3]1[O:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][O:11][CH2:12]C1C=COC=1>>[CH3:10][O:11][CH2:12][C:7]1[CH:6]=[CH:5][O:4][C:3]=1[Sn:2]([CH3:9])([CH3:8])[CH3:1]
Reactant: C[Sn](C)(C)c1ccco1
Reactant: COCc1ccoc1
Product: COCc1ccoc1[Sn](C)(C)C

Procedure:
3-Methoxymethyl-2-trimethylstannylfuran was prepared in the same manner as 2-trimethylstannylfuran with 3-methoxymethylfuran as starting material. bp 93°-97° C. at 15 Torr.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Cl-].[Al+3].[Cl-].[Cl-].[Br:14]Br>O>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:14])=[CH:4][C:3]=1[CH3:9]
Reactant: BrBr
Reactant: Cc1ccc(C)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1cc(Br)c(C)cc1Cl

Procedure:
400 parts of 2-chloro-p-xylene (b.p.=183° to 184° C.) and 2 parts of anhydrous aluminum chloride were charged into a 1-liter four-necked flask provided with a reflux condenser, a thermometer, a stirrer and a dropping funnel, to which 360 parts of bromine was dropwisely added over a period of 5 hours to carry out the reaction at 35° to 60° C. Water was added to the reaction liquid to wash the same with the thus added water and to remove the catalyst, and then the oil layer was cooled. The separated crystals were filtered, and washed with methanol to obtain 377 parts of 2-chloro-5-bromo-p-xylene having a melting point of 60° to 64° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[O:1]([C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: OB(O)c1ccccc1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(Oc2ccccc2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxy-phenyl)-8-trifluoromethylquinolin-3-yl]-phenyl methanone and phenyl boronic acid, following the procedure of Example 519: MS (ESI) m/z 470.
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[C:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:17]=[C:18]([NH:19][CH2:20][C@H:21]([OH:24])[CH2:22][OH:23])[C:13]=3[CH:12]=[C:11]2[C:31]([N:33]2[CH2:38][CH2:37][C:36]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:47])([C:39]#[N:40])[CH2:35][CH2:34]2)=[O:32])(=O)=O)C=CC=CC=1.[OH-].[Na+].Cl>CO>[Cl:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[C:36]1([C:39]#[N:40])[CH2:37][CH2:38][N:33]([C:31]([C:11]2[NH:10][C:14]3[N:15]=[C:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:17]=[C:18]([NH:19][CH2:20][C@H:21]([OH:24])[CH2:22][OH:23])[C:13]=3[CH:12]=2)=[O:32])[CH2:34][CH2:35]1
Reactant: N#CC1(c2ccccc2Cl)CCN(C(=O)c2cc3c(NC[C@H](O)CO)nc(-c4ccccc4)nc3n2S(=O)(=O)c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CC1(c2ccccc2Cl)CCN(C(=O)c2cc3c(NC[C@H](O)CO)nc(-c4ccccc4)nc3[nH]2)CC1
Yield: 66.6 %

Procedure:
(S)-1-[7-Benzene-sulfonyl-4-(2,3-dihydroxypropylamino)-2-phenyl-7H-pyrrolo[2,3-d]-pyrimidine-6-carbonyl]-4-(2-chlorophenyl)piperidine-4-carbonitrile 31.c (55 mg) was stirred in MeOH and treated with 1 M NaOH aqueous solution at rt under nitrogen for 2 h. The resulting mixture was neutralized with 3M HCl aqueous solution (pH=7). The solvent was then removed in vacuo. The residue was dissolved in DCM+MeOH and charged onto a TLC plate. A white foam (29 mg) was obtained in 67% yield. 1H-NMR (200 MHz, CDCl3+MeOH-d4): δ=1.95-2.20 (m, 2H), 2.50-2.70 (m, 2H), 3.40-3.70 (m, 4H), 3.78-3.95 (m, 3H), 4.65-4.78 (m, 2H), 6.75 (s, 1H), 7.25-7.47 (m, 7H), 8.18-8.23 (m, 4H). MS (ES): 531.0 [MH+].
Reaction SMILES: C([O:5][C:6]1[CH:38]=[CH:37][CH:36]=[CH:35][C:7]=1[CH2:8][N:9]([CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)[CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)(C)(C)C>CCOC(C)=O.Cl>[NH2:12][CH2:11][CH2:10][N:9]([CH2:8][C:7]1[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=1[OH:5])[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)NCCN(CCCN1CCC(c2ccccc2)CC1)Cc1ccccc1OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCN(CCCN1CCC(c2ccccc2)CC1)Cc1ccccc1O
Reaction time: 3 h
Yield: 61 %

Procedure:
Compound 24 (0.8 g, 1.52 mmol) was dissolved in 25 mL EtOAc saturated with HCl and stirred for 3 hr. The solvent was evaporated to dryness. The residue was purified on a silica gel TLC plate that was developed in 8% methanolic NH3 (7 M NH3 in methanol/92% CH2Cl2. The product was obtained as white solid (61%). 1H NMR (CDCl3) δ 7.276 (m, 2H, Ar), 7.208 (m, 2H, Ar), 7.165 (m, 2H, Ar), 6.972 (dd, 1H, Ar), 6.822 (dd, 1H, Ar), 6.769 (ddd, 1H, Ar), 3.744 (s, 2H, —CH2), 3.013, (d, 2H, —CH2—), 2.902 (t, 2H, —CH2—), 2.596 (m, 4H, —CH2—CH2), 2.473 (m, 1H, —CH—), 2.356 (t, 2H, —CH2—), 2.023 (ddd, 2H, —CH2—), 1.784 (m, 6H). Mass Spec.=368.27 (M+H)+.