Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[OH-].[Na+].[C:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)(=[O:7])[CH3:6].Br[CH2:17][CH2:18][CH2:19][Cl:20]>C(O)C>[C:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:17][CH2:18][CH2:19][Cl:20])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: ClCCCBr
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)Nc1ccc(OCCCCl)cc1

Procedure:
In a round bottomed flask equipped with magnetic stirring, reflux condenser, and N2 atmosphere was placed ethanol (500 ml), sodium hydroxide (15.0 g), 4-acetamidophenol of Formula XXIII (30.0 g), and 1-bromo-3-chloropropane of Formula XXII (47.0 g) and the mixture was refluxed overnight. Upon cooling off-white crystals were deposited and then collected. The mother liquor was evaporated to dryness and dissolved in CH2Cl2 then washed with H2O, dried, and concentrated to 50 ml. A second crop of crystals were deposited. These were combined with the first crop of crystals and recrystallized from ethanol to give colorless crystals (20.3 g), mp 128°-130° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C@@H:10]1([C:16]([OH:18])=O)[CH2:12][C@@H:11]1[C:13]([OH:15])=[O:14].[CH3:19][NH:20][CH2:21][CH2:22][CH3:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.ClCCl>[CH3:19][N:20]([CH2:21][CH2:22][CH3:23])[C:16]([C@H:10]1[CH2:12][C@H:11]1[C:13]([OH:15])=[O:14])=[O:18]
Reactant: O=C(O)[C@H]1C[C@H]1C(=O)O
Reactant: CCCNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)[C@H]1C[C@H]1C(=O)O
Reaction time: 60 h
Yield: 34.7 %

Procedure:
Add diisopropylethylamine (2.68 mL, 15.4 mmol) and cis-cyclopropane-1,2-dicarboxylic acid (0.50 g, 3.84 mmol) to a slurry of 2-chlorotrityl chloro resin (3.00 g, Nova Bio) in 7:1 dichloromethane:dimethylfomamide (10.0 mL). Stir over night and then filter the slurry. Wash the resin with 17:2:1 dichloromethane:methanol:dimethylformamide (3×20 mL) followed by dichloromethane (3×20 mL). Add the filtered resin to a solution of diisopropylethylamine (1.34 mL, 7.69 mmol), methylpropylamine (0.788 mL, 7.69 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (2.915 g, 7.69 mmol), and HOBT (1.177 g, 7.69 mmol) in dimethylformamide (10 mL) and shake for 2.5 days. Filter and wash the resin with dimethylformamide (3×20 mL) and dichloromethane (5×20 mL). Add trifluoroacetic acid (1 mL) to a slurry of the washed resin in dichloromethane (20 mL). Shake for 45 minutes and filter. Wash the resin with dichloromethane (2×20 mL) and concentrate this filtrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with dichloromethane containing 10-40% of 5% (2:1 methanol:acetic acid) in dichloromethane to provide the title compound (0.247 g, 34.7%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:14][N:15](C)C=O>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:14]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1)#[N:15]
Reactant: CN(C)C=O
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)Cc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 49 %

Procedure:
To a stirred solution of ethyl 2-(4-bromophenyl)acetate (2.1 g, 8.445 mmol) in anhydrous dimethylformamide were added zinc cyanide (1.5 g, 12.668 mmol) and tetrakis(triphenylphosphine) palladium (1.0 g, 0.845 mmol). The reaction mixture was refluxed for overnight then cooled to room temperature. The mixture was filtered using celite pad and the filtrate was evaporated. The residue was diluted with ethylacetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filterate was concentrated under reduced pressure to get the crude. The crude was purified by column chromatography. Ethyl 2-(4-cyanophenyl)acetate (0.8 g) was obtained as 49% yield.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Cl:14])[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30]>C1COCC1>[Cl:1][C:2]1[N:6]([CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[C:5]2[CH:7]=[C:8]([Cl:14])[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1
Reactant: COCCOCCl
Reactant: O=[N+]([O-])c1cc2nc(Cl)[nH]c2cc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCn1c(Cl)nc2cc([N+](=O)[O-])c(Cl)cc21
Reaction time: 2.5 h
Yield: 83.2 %

Procedure:
To a stirred solution of 2,6-dichloro-5-nitro-1H-benzoimidazole (5.43 g, 23.4 mmol), diisopropylethylamine (12.2 mL, 70.2 mmol), and THF (120 mL) was added portionwise 1-chloromethoxy-2-methoxy-ethane (3.30 mL, 28.1 mmol). The reaction mixture was stirred for 2.5 h and concentrated. Water (50 mL) was added to the residue, the mixture was extracted with EtOAc (3×125 mL). The combined organic layers were washed with brine (100 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (20-55% EtOAc/hexanes) to yield the titled compound (6.23 g, 83% yield) as a 1:1 mixture of regioisomers. MS (ESI/CI): mass calcd. for C11H11Cl2N3O4, 319.0; m/z found, 320.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.24 (s, 1H), 8.16 (s, 1H), 7.83 (s, 1H), 7.69 (s, 1H), 5.71 (s, 2H), 5.68 (s, 2H), 3.72-3.64 (m, 4H), 3.57-3.50 (m, 4H), 3.35 (s, 3H), 3.35 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:37][C:38]4[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: ClCc1ccncc1
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(OC)cc23)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccncc4)c(OC)cc23)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A starting compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl) oxy]phenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 4-chloromethylpyridine hydrochloride (41 mg) were dissolved in N,N-hr dimethylformamide (1 ml), and the solution was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC to give 71 mg (yield 71%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([N:17]4[C:21]5=[N:22][CH:23]=[CH:24][CH:25]=[C:20]5[NH:19][C:18]4=[O:26])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[N:6][CH:7]=1.I[CH2:28][CH3:29].O>CN(C=O)C>[CH2:28]([N:19]1[C:20]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[N:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[N:9]=[CH:10]3)[C:18]1=[O:26])[CH3:29]
Reactant: Cc1ccc(-n2ncc3cc(-n4c(=O)[nH]c5cccnc54)ccc32)nc1
Reactant: CCI
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc3c(cnn3-c3ccc(C)cn3)c2)c2ncccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
A mixture of 3-[1-(5-methylpyridin-2-yl)-1H-indazol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (70 mg) and iodoethane (35.1 mg) in DMF (2 mL) was stirred at 50° C. for 3 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane. The product was crystallized from AcOEt/Hexane to give the title compound as white crystals (25.0 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@@H:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(Cl)(=O)C(Cl)=O.[C:29]([Si:33]([CH3:44])([CH3:43])[O:34][CH2:35][CH2:36][N:37]1[CH:41]=[CH:40][C:39]([NH2:42])=[N:38]1)([CH3:32])([CH3:31])[CH3:30].N1C(C)=CC=CC=1C>CN(C)C=O.C(Cl)Cl>[C:29]([Si:33]([CH3:44])([CH3:43])[O:34][CH2:35][CH2:36][N:37]1[CH:41]=[CH:40][C:39]([NH:42][C:14](=[O:15])[C@@H:13]([C:5]2[CH:6]=[CH:7][C:8]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:3]([C:1]#[N:2])[CH:4]=2)[CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[N:38]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(C#N)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
In a round bottom flask was placed (R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (75 mg, 0.23 mmol), methylene chloride (2 mL) and N,N-dimethylformamide (3 drops). To this solution was then added a solution of oxalyl chloride in methylene chloride (2.0 M solution, 130 μL, 0.26 mmol). Upon addition there was gas evolution. This was stirred for 30 min at 25° C. after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 56 mg, 0.23 mmol), 2,6-lutidine (55 μL, 0.46 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 2 h. After this time, the reaction was quenched with a small amount of methanol and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 40% ethyl acetate/hexanes) to afford (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (105 mg, 84%) as a white foam: [α]24589=−11.0° (c=0.20, methanol); ES-HRMS m/e calcd for C27H40N4O4SSi (M+H)+ 545.2613, observed 545.2603; 1H NMR (400 MHz, CDCl3) δ −0.05 (s, 6H, 2×SiCH3), 0.84 (s, 9H, 3×CH3), 1.14 (m, 2H, CH2), 1.46-1.94 (m, 8H, 4×CH2), 2.24 (m, 1H, CH), 3.27 (s, 3H, SO2CH3), 3.59 (t, J=7.6 Hz, 1H, ArCH), 3.87 (t, J=5.3 Hz, 2H, OCH2), 4.08 (t, J=5.3 Hz, 2H, NCH2), 6.62 (d, J=2.2 Hz, 1H, Ar), 7.35 (d, J=2.2 Hz, 1H, Ar), 7.84 (dd, Jm=1.8 Hz, Jo=8.3 Hz, 1H, Ar), 7.91 (brs, 1H, NH), 7.97 (d, Jm=1.8 Hz, 1H, Ar), 8.15 (d, Jo=8.3 Hz, 1H, Ar).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@@H]3CCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCCC[C@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 100 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (55.0 mg, 0.0893 mmol) prepared in Example 168d, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (41.6 mg, 99%) as a colorless solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[CH2:10]([O:12][C:13]([C:15]#[C:16][C:17](OCC)=[O:18])=[O:14])[CH3:11].IC1C=C2C(C(=O)C=C(C(OCC)=O)N2)=C(C)C=1>>[I:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:4]2[C:3]=1[C:17](=[O:18])[CH:16]=[C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])[NH:5]2
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: Cc1cc(N)cc(I)c1
Agent: CCOC(=O)c1cc(=O)c2c(C)cc(I)cc2[nH]1
Product: CCOC(=O)c1cc(=O)c2c(I)cc(C)cc2[nH]1

Procedure:
Treatment of 3-iodo-5-methylaniline (4.1 g) with diethylacetylene dicarboxylate (2.8 ml) as described in Example 1b, gave a mixture (3.0 g) of ethyl 5-iodo-7-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate [δ (360 MHz, DMSO-d6) 1.50 (3H, t, CH2CH3), 2.76 (3H, s, CH3), 4.41 (2H, q, CH2CH3), 6.58 (1H, s, 3-H), 7.74 (1H, s, 6-H) and 7.78 (1H, s, 8-H)] and ethyl 7-iodo-5-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate [δ (360 MHz, DMSO-d6) 1.33 (3H, t, CH2CH3), 2.72 (3H, s, CH3), 4.41 (2H, q, CH2CH3), 6.54 (1H, bs, 3-H), 7.40 (1H, s, 6-H) and 8.20 (1H, s, 8-H)].
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][C:9]([CH3:12])([CH3:11])[CH:8]([OH:13])[C:4]=2[CH:5]=[N:6][CH:7]=1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22]>>[F:14][C:15]1[CH:16]=[C:17]([C:2]2[C:3]3[CH2:10][C:9]([CH3:12])([CH3:11])[CH:8]([OH:13])[C:4]=3[CH:5]=[N:6][CH:7]=2)[CH:18]=[CH:19][C:20]=1[C:21]([F:22])([F:23])[F:24]
Reactant: CC1(C)Cc2c(Br)cncc2C1O
Reactant: OB(O)c1ccc(C(F)(F)F)c(F)c1
Product: CC1(C)Cc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc2C1O

Procedure:
In analogy to the procedure described for the preparation of examples 85 and 86, 4-bromo-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (intermediate A-17) and 3-fluoro-4-trifluoromethyl-phenylboronic acid gave racemic 4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,6-dimethyl-5,7-dihydrocyclopenta[c]pyridin-7-ol. SFC separation afforded (+)-(7R)-4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,6-dimethyl-5,7-dihydrocyclopenta[c]pyridin-7-ol (example 108) and (−)-(7S)-4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,6-dimethyl-5,7-dihydrocyclopenta[c]-pyridin-7-ol (example 109) as white solids. MS: 309.0 (M+H+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][O:38][C:39](=[O:56])[C:40]1[CH:45]=[CH:44][C:43](B2OC(C)(C)C(C)(C)O2)=[CH:42][C:41]=1[F:55].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:37][O:38][C:39](=[O:56])[C:40]1[CH:45]=[CH:44][C:43]([C:19]([C:11]2[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:42][C:41]=1[F:55]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1F
Yield: 71.3 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.55 g, 1 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (1.0 g, 3 mmol) and dichlorobis(triphenylphosphine)palladium (II) (70 mg, 0.1 mmol) in dioxane (6 mL) was added an aqueous sodium carbonate solution (2 M, 1.5 mL). The mixture was subjected to microwave irradiation for 2 h at 100° C. The resulting mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-2-fluoro-benzoic acid methyl ester (360 mg, 68%) as a white solid: LC/MS m/e calcd for C28H25FN2O4S [M+H]+ 505.58, observed 505.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH2:10][OH:11])=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH:10]=[O:11])=[CH:6][CH:7]=1
Reactant: OCC=C(c1ccc(Cl)cc1)c1cccnc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=CC=C(c1ccc(Cl)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
A mixture of 0.30 g 3-(4-chlorophenyl)-3-(3-pyridyl)-2-propen-1-ol and 1.5 g manganese dioxide in 15 ml chloroform was stirred overnight at room temperature under nitrogen. Filtration and evaporation of the solvent gave 0.30 g of a yellow oil, which contained the isomeric aldehydes in a Z/E ratio of circa 60/40 according to NMR. The crude product was used directly in the reductive dimethylamination according to Example 15.
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:35][O:36][C:37]1[C:42]([CH2:43][N:44]2[CH2:49][CH2:48][CH:47]([CH:50]=O)[CH2:46][CH2:45]2)=[CH:41][CH:40]=[CH:39][N:38]=1>CN(C)C=O>[CH3:35][O:36][C:37]1[C:42]([CH2:43][N:44]2[CH2:49][CH2:48][CH:47](/[CH:50]=[CH:9]/[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH3:2])[CH2:46][CH2:45]2)=[CH:41][CH:40]=[CH:39][N:38]=1
Reactant: COc1ncccc1CN1CCC(C=O)CC1
Reactant: Cc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ncccc1CN1CCC(/C=C/c2ccccc2C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
In N,N-dimethylformamide (10 ml) was suspended 1.15 g of [(2-methylphenyl)methyl]triphenylphosphonium bromide. To the suspension was added 288 mg of potassium tert-butoxide, followed by stirring for 15 minutes under ice-cooling. A solution of 500 mg of 1-[(2-methoxy-3-pyridinyl)methyl]-4-piperidinecarboxaldehyde dissolved in 3 ml of N,N-dimethylformamide was added dropwise thereinto, followed by stirring at room temperature overnight. Ice-water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to give 473 mg of the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[N:6][CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=1)[CH3:2].Br[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([CH2:46][C:47]([CH3:54])([CH3:53])[C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:42]([C:55]([F:58])([F:57])[F:56])[CH:41]=2)=[O:38])=[C:32]([F:59])[CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH:39][C:40]3[CH:45]=[CH:44][C:43]([CH2:46][C:47]([CH3:54])([CH3:53])[C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:42]([C:55]([F:56])([F:58])[F:57])[CH:41]=3)=[O:38])=[C:32]([F:59])[CH:31]=2)[CH:7]=[N:6][C:5]=1[O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)Cc1ccc(NC(=O)Cc2ccc(Br)cc2F)cc1C(F)(F)F
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OCc1ccc(OC)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)Cc1ccc(NC(=O)Cc2ccc(-c3cnc(OCc4ccc(OC)cc4)c(OCC)c3)cc2F)cc1C(F)(F)F
Yield: 38.9 %

Procedure:
To a mixture of 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.58 g, 11.90 mmol) and ethyl 3-(4-(2-(4-bromo-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (6 g, 11.90 mmol) in H2O (1 mL) and 1,4-dioxane (3 mL) was added cesium carbonate (7.75 g, 23.79 mmol) and PdCl2(dppf) (0.435 g, 0.595 mmol) under N2. Then the mixture was stirred and irradiated in a microwave oven at 120° C. for 30 min. The mixture was concentrated and extracted with EA. The combined organic layers were concentrated. The crude material was purified on silica column chromatography (PE/EA=5:1). All fractions found to contain product by TLC (PE/EA=2:1, Rf=0.45) were combined and concentrated to yield a yellow solid of ethyl 3-(4-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (4.5 g, 4.63 mmol, 38.9% yield): 1H NMR (400 MHz, CD3OD) δ: 7.98-7.93 (m, 2H), 7.70 (d, J=6.8 Hz, 1H), 7.46-7.35 (m, 6H), 7.23 (d, J=8.6 Hz, 1H), 6.90 (d, J=8.6 Hz, 2H), 5.36 (s, 2H), 4.18-4.10 (m, 4H), 3.83-3.75 (m, 5H), 3.09-3.05 (m, 2H), 1.41 (t, J=7.2 Hz, 3H), 1.24 (d, J=1.8 Hz, 9H); ES-LCMS m/z 563 (M−120).
Reaction SMILES: [CH:1]([Si:4]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[O:5][CH2:6][CH2:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:19]2[CH:20]=[C:21]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31]O)[CH:22]=[CH:23][C:18]2=[N:17][N:16]=1)([CH3:3])[CH3:2].CS(OS(C)(=O)=O)(=O)=O.C([N:50](CC)CC)C.N.CO>C1(C)C=CC=CC=1.O>[CH:36]([Si:4]([CH:1]([CH3:2])[CH3:3])([CH:33]([CH3:34])[CH3:35])[O:5][CH2:6][CH2:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:19]2[CH:20]=[C:21]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][NH2:50])[CH:22]=[CH:23][C:18]2=[N:17][N:16]=1)([CH3:37])[CH3:38].[C:10]1([CH3:15])[CH:11]=[CH:12][CH:13]=[CH:14][CH:9]=1
Reactant: CC(C)[Si](OCCSc1ccccc1-c1nnc2ccc(Sc3ccccc3CO)cn12)(C(C)C)C(C)C
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: N
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)[Si](OCCSc1ccccc1-c1nnc2ccc(Sc3ccccc3CN)cn12)(C(C)C)C(C)C
Temperature: 5 °C
Reaction time: 3 h

Procedure:
To a slurry of benzyl alcohol of Example 8 (25.0 g, 0.044 moles) in toluene (250 ml), was added methanesulfonic anhydride (10.77 g, 0.062 moles) then cooled to 5° C. Triethylamine (6.93 g, 0.068 moles) was added over 30 minutes and stirred at this temperature for 3 hours. The resultant solution was added to 7M ammonia in methanol solution (316 ml, 2.21 moles) and stirred for 16 hours. Water (250 ml) was added and the organic phase washed with water (250 ml). The aqueous phases were extracted with toluene (125 ml) and the combined organics were dried by azeotropic distillation under reduced pressure to leave the title compound as a clear brown solution in toluene (125 ml) (assumed quantitative yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[C:13]([O:17][C:18](=[O:21])[CH:19]=[CH2:20])([CH3:16])([CH3:15])[CH3:14]>CC(O)C>[C:13]([O:17][C:18](=[O:21])[CH2:19][CH2:20][NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:12])([CH3:16])([CH3:15])[CH3:14]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CNCCN
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)CCNCCNCC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 0.1 %

Procedure:
To the solution of (2-amino-ethylamino)-acetic acid tert-butyl ester (1.0 mL, 6.32 mmol) in i-PrOH (50 mL) was added acrylic acid tert-butyl ester (309.1 μL, 2.11 mmol). The suspension was heated for 48 hours at 60° C. The solvent was evaporated and product was purificated by column chromatography (DCM-MeOH—NH3=90:3:0.5) yielded the title product as colorless oil (0.45 mg).