Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1(/[CH:9]=[CH:10]/[CH2:11]O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[S:13]([O-])(=[O:16])(=[O:15])[CH3:14]>>[CH3:1][O:2][C:3]1(/[CH:9]=[CH:10]/[CH2:11][S:13]([CH3:14])(=[O:16])=[O:15])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC1(/C=C/CO)CCOCC1
Reactant: CS(=O)(=O)[O-]
Product: COC1(/C=C/CS(C)(=O)=O)CCOCC1

Procedure:
4-methoxy-4-(3-hydroxy-trans-prop-1-enyl)tetrahydropyran, prepared as in Example 3, was converted to the corresponding mesylate according to the method of Crossland and Servis, J. Org. Chem., 35, 3195-3196 (1970).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4](Cl)=[C:5]2[C:9](=[O:10])[CH2:8][CH2:7][C:6]=12.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C([O-])(O)=O.[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[S:3][C:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[F:12])=[C:5]2[C:9](=[O:10])[CH2:8][CH2:7][C:6]=12
Reactant: O=C1CCc2c(Cl)sc(Cl)c21
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: O=C1CCc2c(Cl)sc(-c3ccccc3F)c21
Yield: 36.6 %

Procedure:
To a stirred solution of 1,3-dichloro-5,6-dihydro-4H-cyclopenta(c)thiophene-4-one (250 mg, 1.21 mmol) in DME (7.5 mL) was added 2-fluorobenzeneboronic acid (177 mg, 1.27 mmol), saturated aqueous NaHCO3 solution (2.5 mL) and bis(triphenylphosphine)palladium(II)chloride (100 mg, 0.14 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 8 hours. The whole was extracted with ethyl acetate (50 mL×2), and the combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with hexane-ethyl acetate (10:1) to provide the subtitle compound (118 mg, 37% yield).
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[CH2:9][C@:10]2([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:14]#[N:15])(C)(C)C.[CH2:24]([Mg]Br)[CH3:25].C(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1.C1COCC1>[NH2:15][CH:14]([C@@:10]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:9][C@@H:8]2[CH2:13][C@H:11]1[CH2:12][CH:7]2[OH:6])[CH2:24][CH3:25]
Reactant: CC[Mg]Br
Reactant: CC(C)(C)[Si](C)(C)OC1C[C@@H]2C[C@H]1C[C@@]2(C#N)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCC(N)[C@@]1(c2ccccc2)C[C@@H]2C[C@H]1CC2O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
930 mg (2.8 mmol) of (1S,2S,4S)-5-(tert-Butyl-dimethyl-silanyloxy)-2-phenyl-bicyclo[2.2.1]heptane-2-carbonitrile (88) were dissolved in 10 mL of anhydrous toluene. Afterwards, 5.7 mL of a 1M solution of ethylmagnesium bromide in THF was added and the mixture was heated under reflux for 12 h. The mixture was then treated with 3 mL ethanol and evaporated. The residue was dissolved in 20 mL of ethanol and 215 mg (5.7 mmol) of NaBH4 was added. The mixture was stirred at ambient temperature for 3 h and then evaporated. The residue was dissolved using 100 mL of water, the pH adjusted to 3 using aqueous HCl-solution to remove excess NaBH4 and then adjusted to pH=12 using saturated aqueous Na2CO3-solution. The mixture was extracted three times using 30 mL of t-butylmethylether each. Afterwards, the organic layer was extracted twice using 20 mL of a 1N aqueous HCl-solution each, the aqueous layer was adjusted to pH>11 using saturated aqueous Na2CO3-solution and extracted three times using 30 mL t-butylmethylether each. The organic layer was dried using MgSO4 and evaporated yielding 200 mg of the desired product 89, used without further purification. Rt=0.58 min (Method 18).
Reaction SMILES: [OH:1][CH:2]([CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:3]#[N:4].[CH3:21]I.[H-].[Na+]>CN(C=O)C.O>[CH3:21][O:1][CH:2]([CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:3]#[N:4]
Reactant: CI
Reactant: COc1ccccc1OC(c1ccccc1)C(O)C#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1OC(c1ccccc1)C(C#N)OC
Yield: 68.9 %

Procedure:
2.69 g of 2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)-propionitrile dissolved in 25 ml of anhydrous DMF and 7.1 g of methyl iodide were stirred at 0° C. Addition was made, in portions, of 2.18 g of 55% NaH. After the addition, the whole was stirred at 0°-5° C. for 1 and a half hours. Under an atmosphere of nitrogen the whole was then decomposed cautiously with water, diluted with plentiful water, extracted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4 and evaporated to dryness, in this way obtaining 1.95 g of 2-methoxy-3-phenyl-3-(2-methoxy-phenoxy)-propionitrile as an oil. Yield=69%.
Reaction SMILES: C(OC(Cl)=O)C(C)C.C(OC([NH:16][C@H:17]([C:22](O)=O)[C@@H:18]([CH3:21])[O:19][CH3:20])=O)(C)(C)C.CN1CCOCC1.[NH2:32][C:33]1[C:38]([NH2:39])=[CH:37][C:36]([C:40]2[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=2)=[C:35]([F:48])[CH:34]=1>C1COCC1.CC(O)=O.C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:16][C@H:17]([C:22]1[NH:32][C:33]2[CH:34]=[C:35]([F:48])[C:36]([C:40]3[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=3)=[CH:37][C:38]=2[N:39]=1)[C@H:18]([O:19][CH3:20])[CH3:21]
Reactant: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#Cc1ccc(-c2cc(N)c(N)cc2F)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CO[C@H](C)[C@H](N)c1nc2cc(-c3ccc(C#N)cc3)c(F)cc2[nH]1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Isobutylchloroformate (0.17 g, 0.125 mmol) was added to a cooled mixture of N-(tert-butoxycarbonyl)-O-methyl-L-threonine (Preparation 51, 0.28 g, 0.12 mmol) and NMM (0.137 g, 0.135 mmol) in THF (10 mL) at −78° C. The reaction was stirred at this temperature for 1 hour and then added dropwise to a cooled solution of 4′,5′-diamino-2′-fluorobiphenyl-4-carbonitrile (Preparation 76, 0.28 g, 0.12 mmol) at −78° C. and stirred at this temperature for 3 hours. The reaction was partitioned between EtOAc (70 mL) and saturated aqueous NaHCO3 solution (30 mL), the organic layer was collected and concentrated in vacuo to afford a brown residue that was dissolved in AcOH (5 mL) and heated to 40° C. for 2 days followed by 50° C. for 1 day. The reaction was concentrated in vacuo and purified using silica gel column chromatography to afford a beige solid that was dissolved in TFA/DCM (0.2 mL/3 mL) and stirred at room temperature for 5 hours. The reaction was partitioned between saturated aqueous Na2CO3 solution (10 mL) and EtOAc (30 mL). The organic layer was collected and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with a gradient of acetonitrile in 0.5% formic acid in water followed by elution through an SCX cartridge to afford the title compound that contains some of the other diastereomer.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11]([C:13]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:14]=2[O:15][CH2:16][C@@H:17]2[CH2:20][CH2:19][N:18]2[C:21](OC(C)(C)C)=O)=[O:12])/[N:7]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C=O.C(O)=O.[C:45]1([CH3:55])[CH:50]=[CH:49][C:48]([S:51]([OH:54])(=[O:53])=[O:52])=[CH:47][CH:46]=1.O>CCOC(C)=O>[C:45]1([CH3:55])[CH:46]=[CH:47][C:48]([S:51]([OH:54])(=[O:52])=[O:53])=[CH:49][CH:50]=1.[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:12])[C:13]2[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[CH:28][C:14]=2[O:15][CH2:16][C@@H:17]2[CH2:20][CH2:19][N:18]2[CH3:21])/[N:7]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1OC[C@@H]1CCN1C(=O)OC(C)(C)C
Agent: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=CO
Product: CC(C)Cn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1OC[C@@H]1CCN1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A solution of the product of Example 12B (0.45 g, 0.79 mmol) in formaldehyde (2 mL, 72.6 mmol) and formic acid (4 mL, 104 mmol) was warmed to 100° C. and was allowed to stir for 2 h then was cooled to ambient temperature and was concentrated under reduced pressure. The mixture was purified via column chromatography (SiO2, 100% CH2Cl2 to 9:1:0.1 CH2Cl2:CH3OH:NH4OH). The free amine was dissolved in EtOAc (1 mL) and p-toluenesulfonic acid-H2O (1 eq) in EtOAc (1 mL) was added. The p-toluenesulfonic acid salt of the title compound (0.25 g, 0.38 mmol, 48% yield) was isolated via filtration. 1H NMR (300 MHz, CD3OD) δ ppm 0.98 (dd, J=6.6, 2.2 Hz, 6H), 1.39 (s, 9H), 2.27-2.34 (m, 1H), 2.36 (s, 3H), 2.55-2.76 (m, 2H), 3.06 (s, 3H), 3.98-4.18 (m, 3H), 4.26-4.37 (m, 1H), 4.50 (d, J=3.4 Hz, 2H), 4.73-4.80 (m, 1H), 7.19-7.26 (m, 3H), 7.34 (d, J=8.8 Hz, 1H), 7.67-7.73 (m, 2H), 7.79 (dd, J=8.8, 2.0 Hz, 1H), 8.39 (d, J=2.0 Hz, 1H); MS (DCI/NH3) m/z 484 (M+H)+. Anal. calculated for C24H32F3N3O2S.C7H8O3S.0.2H2O: Calc: C, 56.47; H, 6.18; N, 6.37. Found: C, 56.19; H, 6.28; N, 6.38.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:12]1([CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Mg]Cl.[NH4+].[Cl-].[O-][Mn](=O)(=O)=O.[K+]>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH3:20])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: CNC(=O)c1ccc(Cl)nc1
Reactant: Cc1ccccc1[Mg]Cl
Agent: O=[Mn](=O)(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)c1cnc(Cl)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
A solution of 1.5 g (8.8 mmol) 6-chloro-N-methyl-nicotinamide in 18 ml THF was added at 4° C. over 15 min to a solution of 21.9 ml (21.9 mmol) o-tolylmagnesium chloride 1M in THF. The reaction mixture was stirred at r.t. for 2 h cooled to 4° C. and treated dropwise over 10 min with 30.0 ml 5% aqueous NH4Cl. The aqueous phase was separated and extracted twice with THF and the organic phases were washed twice with 5% aqueous NH4Cl. The combined organic phases were dried over Na2SO4 and subsequently treated at r.t. in four portions over 10 h with 0.9 g (5.7 mmol) KMnO4. The reaction mixture was stirred for 5.5 h at r.t., filtrated and the solvent was removed. The residue was purified by chromatography over silica gel (CHCl3) to yield 1.8 g (78.9%) product as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:2]1.[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][CH2:29][C:30](O)=[O:31])[CH:24]=[C:25]([F:27])[CH:26]=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>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][CH2:29][C:30]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]3[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]4[NH:17][CH:18]=[CH:19][C:9]=34)[CH2:2]2)=[O:31])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: O=C(O)CNc1cc(F)cc(Cl)c1
Reactant: NC(=O)c1cnc2[nH]ccc2c1NC1CCCNC1
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: NC(=O)c1cnc2[nH]ccc2c1NC1CCCN(C(=O)CNc2cc(F)cc(Cl)c2)C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 48.5 %

Procedure:
To a solution of 4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (132 mg, 0.51 mmol, 1.0 eq) and 2-((3-chloro-5-fluorophenyl)amino)acetic acid (124 mg, 0.61 mmol, 1.2 eq) in DMF (3 mL) was added HBTU (387 mg, 1.02 mmol, 2.0 eq) and DIPEA (1 mL). The resulting mixture was stirred at 80° C. for 16 h and the solvent was concentrated in vacuo to afford a residue which was purified by prep-HPLC (MeOH/H2O with 0.05% TFA as mobile phase) to give afford the title compound as a light brown solid (110 mg, yield: 50%). 1H NMR (400 MHz, CD3OD) δ: 8.23 (s, 1H), 7.09-7.02 (m, 1H), 6.66-6.61 (m, 1H), 6.42-5.94 (m, 3H), 4.35-4.10 (m, 1H), 4.08-3.91 (m, 2H), 3.79-3.74 (m, 1H), 3.65-3.53 (m, 2H), 3.43-3.40 (m, 2H), 2.06-2.04 (m, 1H), 1.82-1.73 (m, 2H), 1.62-1.59 (m, 1H). ESI-MS (M+H)+: 445.15.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:15]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:11]([Cl:32])[CH:10]=1)C1C=CC=CC=1.Cl.C(O)(=O)C>[C].[Pd].CN(C)C=O>[Cl:32][C:11]1[CH:10]=[C:9]([OH:8])[CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:15]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CCCCn1c(C(=O)OCC)cc2c(Cl)cc(OCc3ccccc3)cc21
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)CCCCn1c(C(=O)OCC)cc2c(Cl)cc(O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
A mixture of ethyl 6-benzyloxy-4-chloro-1-(4-ethoxycarbonylbutyl)-1H-indolecarboxylate (15.0 g, 32.8 mmol), 35% hydrochloric acid (3.3 ml), acetic acid (240 ml), 10% palladium-carbon (1.5 g) and N,N-dimethylformamide (60 ml) was stirred under a hydrogen atmosphere at room temperature for about 1 hour. The catalyst was filtered off and the filtrate was poured into a cooled 5% aqueous sodium chloride solution and extracted twice with ethyl acetate. The extract solution was washed three times with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was crystallized from toluene to obtain 6.57 g of ethyl 4-chloro-1-(4-ethoxycarbonylbutyl)-6-hydroxy-1H-indolecarboxylate.
Reaction SMILES: OC(C1N=C(CCC)NC=1C(OCOC(=O)C(C)(C)C)=O)(C)C.[OH:24][C:25]([C:28]1[N:29]=[C:30]([CH2:36][CH2:37][CH3:38])[NH:31][C:32]=1[C:33]([OH:35])=[O:34])([CH3:27])[CH3:26].[CH:39]([O:42][C:43]([O:45][CH2:46]Cl)=[O:44])([CH3:41])[CH3:40]>>[OH:24][C:25]([C:28]1[N:29]=[C:30]([CH2:36][CH2:37][CH3:38])[NH:31][C:32]=1[C:33]([O:35][CH2:46][O:45][C:43]([O:42][CH:39]([CH3:41])[CH3:40])=[O:44])=[O:34])([CH3:27])[CH3:26]
Reactant: CC(C)OC(=O)OCCl
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)[nH]1
Agent: CCCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)[nH]1
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)OC(C)C)[nH]1
Yield: 74.4 %

Procedure:
Following a procedure similar to that described in Preparation 22(ii), but using 1.06 g of 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid [prepared as described in Preparation 22(i)] and 0.83 g of isopropoxycarbonyloxymethyl chloride, 1.22 g of the title compound, melting at 144°-146° C., were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=3[N:14]=[C:13]2[CH2:22]Cl)[CH2:9]1)=O)(C)(C)C.[CH3:24][S:25]([C:28]1[C:36]2[C:31](=[CH:32][N:33]=[CH:34][CH:35]=2)[NH:30][N:29]=1)(=[O:27])=[O:26]>>[NH:8]1[CH2:9][CH:10]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=3[N:14]=[C:13]2[CH2:22][N:30]2[C:31]3=[CH:32][N:33]=[CH:34][CH:35]=[C:36]3[C:28]([S:25]([CH3:24])(=[O:26])=[O:27])=[N:29]2)[CH2:11]1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Reactant: CC(C)(C)OC(=O)N1CC(n2c(CCl)nc3cc(Cl)ccc32)C1
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CNC2)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 2-13 by using 3-(5-chloro-2-chloromethyl-benzoimidazol-1-yl)-azetidine-1-carboxylic acid tert-butyl ester and 3-methanesulfonyl-1H-pyrazolo[3,4-c]pyridine instead of 3-(5-chloro-2-chloromethyl-benzoimidazol-1-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester and 3-methanesulfonyl-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: CO.C([O:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[S:13][C:14]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([F:23])[C:15]=2[N:16]=1)C.[OH-].[Na+]>O>[F:23][C:17]1[C:15]2[N:16]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:24])=[O:5])[S:13][C:14]=2[C:20]([F:21])=[CH:19][C:18]=1[F:22]
Reactant: CCOC(=O)CCCCCc1nc2c(F)c(F)cc(F)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
To methanol (3 ml) was added 6-(4,5,7-trifluorobenzothiazol-2-yl)hexanoic acid ethyl ester (390 mg, 1.18 mmol) and aqueous 2N sodium hydroxide (0.7 ml, 1.4 mmol) and the mixture was stirred at room temperature for 1 hour. The resultant reaction mixture was diluted with water and washed with ether. The aqueous phase was acidified with 7% hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried and then evaporated to yield a residue, which was crystallized from hexane-isopropyl ether to give 6-(4,5,7-trifluorobenzothiazol-2-yl)hexanoic acid (170 mg, 48%) as a colorless powder.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH:2]1[O:4][CH2:3]1.[NH:16]1[CH:21]=[CH:20][CH:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH2:18][CH2:17]1>>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([C:19]2[CH2:20][CH2:21][N:16]([CH2:3][CH:2]([OH:4])[CH2:1][N:5]3[C:13]4[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=4)[CH:7]=[CH:6]3)[CH2:17][CH:18]=2)=[CH:23]1
Reactant: COc1cccc2c1ccn2CC1CO1
Reactant: C1=CC(c2c[nH]c3ccccc23)CCN1
Product: COc1cccc2c1ccn2CC(O)CN1CC=C(c2c[nH]c3ccccc23)CC1
Yield: 60.6 %

Procedure:
A methanolic solution of 1-N-glycidyl-4-methoxyindole (0.6 g, 3.0 mmole) from example 2 and 3-(4-tetrahydropyridinyl)indole (0.59 g, 3.0 mmole) was refluxed under nitrogen for 15 hours. The reaction mixture was concentrated in vacuo and the product purified by flash silica gel chromatography (ethyl acetate) to afford the titled compound as a yellow colored solid (0.73 g, 60% yield). Treatment with a 0.25M ethanolic solution of fumaric acid (0.5 equivalents) gave the required product as a yellow colored solid. The product was recrystallized from ethanol.
Reaction SMILES: [C:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[N:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=1)(=[O:3])[CH3:2].CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[CH3:25][N:26]([CH3:28])/[CH:27]=[CH:2]/[C:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[N:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1cc(C(C)=O)n(Cc2cccc(OC)c2)n1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C(=O)/C=C/N(C)C)n(Cc2cccc(OC)c2)n1
Temperature: 140 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 5-acetyl-1-(3-methoxy-benzyl)-1H-pyrazole-3-carboxylate (300 mg, 1 mmol) in 2 mL toluene, 240 mg (2 mmol) of N,N-dimethylformamide dimethyl acetal were added. The mixture was stirred for 18 h at 140° C. The volatiles were removed under vacuum to afford the title compound in quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O>>[Br:24][C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:10][C:11]=1[CH3:13]
Reactant: Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)c1
Reactant: O=C1CCC(=O)N1Br
Product: Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)c1Br

Procedure:
Following a procedure similar to that described in Example 35, but using 1-(4-fluorophenyl)-4-methyl-2-(4-methylsulfonylphenyl)pyrrole (prepared as described in Example 34) and N-bromosuccinimide as starting materials, the title compound was obtained as a white powder (yield 30%), melting at 158-159° C.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.[C:16]([NH:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][CH3:27])=[O:25])=[C:22]([NH:30][C:31]2[C:36]([Cl:37])=[CH:35][N:34]=[C:33](Cl)[N:32]=2)[CH:21]=1)(=[O:18])[CH3:17]>>[C:16]([NH:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][CH3:27])=[O:25])=[C:22]([NH:30][C:31]2[C:36]([Cl:37])=[CH:35][N:34]=[C:33]([NH:1][C:2]3[CH:15]=[CH:14][C:5]4[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=4[CH:3]=3)[N:32]=2)[CH:21]=1)(=[O:18])[CH3:17]
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: CNC(=O)c1ccc(NC(C)=O)cc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccc(NC(C)=O)cc1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl

Procedure:
4-Acetylamino-2-[5-chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide was prepared from 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 4-Acetylamino-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a white powder, 27 mg, 35%. MP>300, LCMS: 522.21 (M+H), HPLC purity 100%, 1H-NMR (DMSO-d6, 400 MHz) δ 11.60 (s, 1H), 9.99 (s, 1H), 9.39 (s, 1H), 9.27 (s, 1H), 8.61 (d, J=4.5 Hz, 1H), 8.53 (s, 1H), 8.23 (s, 1H), 7.72-7.68 (m, 2H), 7.57 (d, J=8.8 Hz, 1H), 7.50 (s, 1H), 6.78 (d, J=8.6 Hz, 1H), 2.78 (d, J=3.9 Hz, 3H), 2.15-2.13 (m, 2H), 2.03 (s, 3H), 1.98-1.96 (m, 2H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8]CC)=[CH2:7])CCC.Br[C:20]1[C:21]([O:29][CH3:30])=[N:22][CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1.C(=O)([O-])O.[Na+]>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.CC(N(C)C)=O>[CH3:30][O:29][C:21]1[C:20]([C:6](=[O:8])[CH3:7])=[CH:25][C:24]([N+:26]([O-:28])=[O:27])=[CH:23][N:22]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ncc([N+](=O)[O-])cc1Br
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: CC(=O)N(C)C
Product: COc1ncc([N+](=O)[O-])cc1C(C)=O

Procedure:
Pd(PPh3)4 (60 mg) and tributyl (1-ethoxyvinyl)tin were added to a DMAc (3 ml) solution containing 3-bromo-2-methoxy-5-nitropyridine (69 mg) obtained in the 1st step, followed by microwave irradiation (Initiator™, 180° C., 10 minutes, 2.45 GHz, 0-240 W). Saturated sodium hydrogen carbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=9:1 to 3:7). A light yellow solid of 1-(2-methoxy-5-nitropyridin-3-yl)ethanone (72 mg) was thus obtained.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Br[CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(O)C>[OH:15][CH2:14][CH2:13][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: OCCBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1cc(C=O)ccc1OCCO
Yield: 40 %

Procedure:
25.9 g (170 mmol) vanillin (Aldrich), 33.3 g (266 mmol) 2-bromoethanol (Aldrich), 35.2 g (255 mmol) potassium carbonate (Sigma-Aldrich), and 20 g molecular sieves (Aldrich) were combined in a 1 liter round bottom flask equipped with magnetic stirrer and nitrogen inlet. Acetone (600 ml) (Chromasolv for HPLC, >99.9%, Sigma-Aldrich) was added and the reaction mixture was refluxed for 16 hours using an external glycerol heating bath set to 65° C. The solids were filtered and the solvent was removed via rotary evaporation to yield a yellow oil. White crystals were obtained by recrystallization in ethyl alcohol at −20° C. (40% yield).