Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]([CH2:20]Cl)[C:16](=[O:22])[CH:15]=2)=[CH:10][CH:9]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[C:34]([O:38][P:39]([O-:46])([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])([CH3:37])([CH3:36])[CH3:35].[K+].C(OCC)(=O)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]([CH2:20][O:46][P:39](=[O:40])([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])[O:41][C:42]([CH3:43])([CH3:44])[CH3:45])[C:16](=[O:22])[CH:15]=2)=[CH:10][CH:9]=1)=[O:5]
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Reactant: O=C(NCc1ccc(-c2ccn(CCl)c(=O)c2)cc1)c1c(Cl)cccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OP(=O)(OCn1ccc(-c2ccc(CNC(=O)c3c(Cl)cccc3Cl)cc2)cc1=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 4 h

Procedure:
2,6-Dichloro-N-[4-(1-chloromethyl-2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-benzamide from the previous step was dissolved in 50 mL DMF. Potassium carbonate (1 g) was added followed by potassium di(t-butyl)phosphate (2 g) and tetrabutylammonium iodide (50 mg). The mixture was stirred at 70° C. for four hours after which it was poured into 300 mL ethyl acetate. The organic phase was washed with water and brine, dried with magnesium sulfate and evaporated under vacuum. The crude product was further purified by silica gel chromatography (eluent: ethyl acetate), giving phosphoric acid di-tert-butyl ester 4-{4-[(2,6-dichloro-benzoylamino)-methyl]-phenyl}-2-oxo-2H-pyridin-1-ylmethyl ester as a colorless oil which slowly crystallized.
Reaction SMILES: Cl[C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[N:17]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:10]3[N:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:18]1([N:17]2[C:10]3[N:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[CH2:6][C:5]2[CH:24]=[CH:25][C:2]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[CH:3][CH:4]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CN1CCNCC1
Reactant: N#Cc1ncc2cc(Cc3ccc(Cl)cc3)n(C3CCCCC3)c2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(Cc3cc4cnc(C#N)nc4n3C3CCCCC3)cc2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
A mixture of 6-(4-chloro-benzyl)-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (1.5 mmol), 1-methylpiperazine (1.8 mmol), cesium carbonate (1.4 mmol), 2-(di-t-butylphosphino)-biphenyl (0.3 mmol) and palladium (II) acetate in toluene (6 ml) is stirred at 100° C. for 3 h. After the reaction mixture is quenched with saturated ammonium chloride, the mixture is extracted with AcOEt. The organic layer is washed with brine, dried over magnesium sulfate and evaporated down. The crude product is applied to a silica gel column chromatography, which is eluted with following solvents: 2% MeOH in CH2Cl2 and 3% MeOH in CH2Cl2. The solvent of the latter effluent is removed by evaporation and dried in vacuo to afford the title compound. yield 40.0%,
Reaction SMILES: CN.[C:3]([C:5]1[CH:6]=[C:7]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([F:22])=[C:17]([CH:21]=2)[C:18]([OH:20])=O)[CH:8]=[N:9][CH:10]=1)#[N:4].O.O[N:25]1[C:29]2C=CC=CC=2N=N1>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[C:3]([C:5]1[CH:6]=[C:7]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([F:22])=[C:17]([CH:21]=2)[C:18]([NH:25][CH3:29])=[O:20])[CH:8]=[N:9][CH:10]=1)#[N:4]
Reactant: On1nnc2ccccc21
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(C(=O)O)c2)c1
Agent: CN
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C#Cc2cncc(C#N)c2)ccc1F
Reaction time: 2 h
Yield: 68 %

Procedure:
Add N-(3-dimethylaminopropyl)-N-ethylcarbdiimide hydrochloride (120 mg, 0.62 mmol) to a mixture of methylamine (19 mg, 310 μL of a 2.0 M stock solution in tetrahydrofuran, 0.62 mmol), 5-(5-cyanopyridin-3-ylethynyl)-2-fluorobenzoic acid), (prepared as described in EXAMPLE 120), (150 mg, 0.56 mmol) and 1-hydroxybenzotriazole hydrate (76 mg, 0.56 mmol) in N,N-dimethylformamide (2 mL), and stir for 2 h. Dilute the reaction mixture with ethyl acetate and an aqueous saturated solution of sodium bicarbonate and separate the layers. Extract the aqueous phase once with ethyl acetate. Wash the combined organic phases once with an aqueous saturated solution of sodium chloride, dry (sodium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with 20:80 ethyl acetate:dichloromethane, to give the title compound as a white solid (107 mg, 68%).
Reaction SMILES: [Cl:1][C:2]([Cl:15])([Cl:14])[CH:3]([C:5]1[C:13]2[S:12][N:11]=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)[OH:4]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:15][C:2]([Cl:1])([Cl:14])[C:3]([C:5]1[C:13]2[S:12][N:11]=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: OC(c1cccc2nnsc12)C(Cl)(Cl)Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=C(c1cccc2nnsc12)C(Cl)(Cl)Cl

Procedure:
A solution of 2.8 g of 7-(1,1,1-trichloro-2-hydroxyeth-2-yl)benzo-1,2,3-thiadiazole in 30 ml of chloroform is treated with 5 g of manganese dioxide and refluxed for 16 hours, with stirring. A further 5 and 3 g of manganese dioxide are added at intervals of 16 hours and 8 hours, respectively. After a total of 40 hours, the mixture is cooled and filtered twice through Hyflo, the filtrate is evaporated and purified using silica gel (hexane/ethyl acetate 7:3), giving the title compound of refractive index nD26 =1.6178.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22]([O:24]C)=[O:23])[CH:4]=1)#[N:2].[OH-].[K+]>O.CO>[C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22]([OH:24])=[O:23])[CH:4]=1)#[N:2]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Yield: 84.2 %

Procedure:
8.8 g of methyl 3-cyanoandrosta-3,5-diene-17β-carboxylate [prepared as described in step (a) above] and 4.3 g of potassium hydroxide were dissolved in a mixture of 20 ml of water and 200 ml of methanol, and the resulting solution was heated under reflux for 10 hours. At the end of this time, the methanol in the reaction mixture was removed by distillation under reduced pressure, the mixture was made acidic by the addition of dilute aqueous hydrochloric acid and extracted three times with methylene chloride. The organic extract was washed with water and then with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. In was then concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through 150 g of silica gel using a gradient elution method, with mixtures of acetone and methylene chloride in ratios ranging from 2:98 to 16:84 by volume as the eluent, to give 7.1 g of the title compound.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[F:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][Mg]Cl)=[CH:18][CH:17]=1>O1CCCC1>[F:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][C:3]([C:5]2[N:6]=[CH:7][CH:8]=[CH:9][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[O:4])=[CH:18][CH:17]=1
Reactant: Fc1ccc(C[Mg]Cl)cc1
Reactant: COC(=O)c1cccnc1C(=O)OC
Solvent: C1CCOC1
Product: COC(=O)c1cccnc1C(=O)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of dimethylpyridine-2,3-dicarboxylate (1.0 g, 5.1 mmol) in tetrahydrofuran (50 ml) was added (4-fluorobenzyl)magnesium chloride (0.25 M in tetrahydrofuran, 20 ml, 5.1 mmol) through a syringe at −78° C. The reaction mixture was stirred at the same temperature for 30 minutes and was quenched with addition of water. After warming up to room temperature, the reaction mixture was partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated. The residue was purified by flash chromatography (15% ethyl acetate in hexane) to give the title compound. MS (DCI/NH3) m/z 274 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C.C(Cl)Cl.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>>[CH3:20][N:17]1[CH2:18][CH2:19][N:14]([CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH2:15][CH2:16]1.[C:26]([OH:28])([C:25]([F:30])([F:29])[F:24])=[O:27]
Reactant: CN1CCN(C2CCCN(C(=O)OC(C)(C)C)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(C2CCCNC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-Methyl-piperazin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (2.25 g, 7.94 mmol) was dissolved in Methylene chloride (50.0 mL, 7.80E2 mmol) and the reaction mixture was treated with Trifluoroacetic Acid (6.0 mL, 78 mmol). The reaction was allowed to stir overnight at room temperature. The solvent was then removed en vacuo to afford 1-Methyl-4-piperidin-3-yl-piperazine as a TFA salt. The crude product contained excess TFA, which was neutralized in the next synthetic step. (M+H)=184.09.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[N:7][O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:27]=[C:26]([S:28]([CH3:30])=[O:29])[C:25]([F:31])=[CH:24][C:23]=1F.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CS(C)=O>[CH:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][N:7]=[C:4]2[CH2:3][CH2:2][N:1]([C:23]3[CH:24]=[C:25]([F:31])[C:26]([S:28]([CH3:30])=[O:29])=[CH:27][C:22]=3[F:21])[CH2:6][CH2:5]2)[CH2:14][CH2:13]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CS(=O)c1cc(F)c(F)cc1F
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(S(C)=O)cc3F)CC2)CC1
Temperature: 120 °C

Procedure:
2d (0.78 g, 1.76 mmol) and 43b (0.66 g, 3.39 mmol) were combined with diisopropylethylamine (0.91 mL, 5.5 mmol) in DMSO (8 mL) and heated to 120° C. overnight. The mixture was cooled to room temperature and poured into 20 mL of ethyl acetate, washed with water (20 mL) and brine (3×20 mL), dried and concentrated. The residue was purified by flash chromatography (eluent: 50 to 90% of EtOAc+0.1% triethylamine in hexane) to afford 4-[1-(2,5-difluoro-4-methanesulfinyl-phenyl)-piperidin-4-ylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester 43-1. This material was recrystallized from toluene and hexane to afford 43-1 as a white powder: HPLC, LC-MS 458.1 (MH), tR=6.98 (Method 2). EC50: 58 nM.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C@@H:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14](O)[CH:15]=[CH:16][CH:17]=1.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>O1CCCC1>[F:11][C:12]1[CH:17]=[C:16]([CH:15]=[CH:14][CH:13]=1)[O:10][C@@H:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=1)[CH3:9]
Reactant: Oc1cccc(F)c1
Reactant: C[C@H](O)c1ccnc(N)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1cccc(F)c1)c1ccnc(N)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47.7 %

Procedure:
(S)-1-(2-aminopyrimidin-4-yl)ethanol (6b) (7.75 g), 3-fluorophenol (6.87 g) and triphenylphosphine (16.07 g) were added to tetrahydrofuran (150 mL) under nitrogen and cooled to 0° C. (brine/ice bath). The resulting brown mixture was stirred at 0° C. for 20 min then diisopropyl azodicarboxylate (12.06 mL, 12.39 g) was added dropwise as a solution in tetrahydrofuran (40 mL). The reaction was maintained at 0-2° C. throughout the addition and was then allowed to warm to room temperature overnight. The solvent was removed under reduced pressure before the crude product was loaded onto a silica plug and purified by flash chromatography on silica eluting with heptane/ethyl acetate 7:3 followed by crystallisation from ethanol to give the title compound (6.2 g) as a white crystalline solid, MS (ES): m/z 234.0 [M+H]+; [α]D−153.0 (methanol, c=1.8 mg/ml).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]([N:12]2[C:16]([CH3:18])([CH3:17])[CH2:15][O:14][C:13]2=[O:19])[S:10][CH:11]=1)(=O)=O.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(N(CC)CC)C>O1CCCC1.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>[CH3:18][C:16]1([CH3:17])[CH2:15][O:14][C:13](=[O:19])[N:12]1[C:9]1[S:10][CH:11]=[C:7]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=2)[N:8]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC1(C)COC(=O)N1c1nc(OS(=O)(=O)C(F)(F)F)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Reaction time: 16 h

Procedure:
A vial under nitrogen was charged with 2-(4,4-dimethyl-2-oxo-1,3-oxazolidin-3-yl)-1,3-thiazol-4-yl trifluoromethanesulfonate (100 mg, 0.28 mmol), [4-(trifluoromethyl)phenyl]-boronic acid (58 mg, 0.31 mmol), and tetrakis(triphenylphosphine)palladium (65 mg, 0.056 mmol) followed by tetrahydrofuran (0.6 mL) and triethylamine (0.13 mL, 0.92 mmol). The mixture was stirred for 16 h, diluted with tetrahydrofuran, passed through a plug of silica gel (2 g) and concentrated. The crude product was purified by reverse phase HPLC to give the title compound. HRMS: calcd for C15H13F3N2O2S+H+, 343.07226; found (ESI-FT/MS, [M+H]1+), 343.0725; Analytical HPLC: purity 100% at 210-370 nm, 10.7 min; 100% at 268 nm, 10.7 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:34])[CH:21]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])C.[OH-].[Na+].CO>C1COCC1>[CH3:32][C:29]([CH3:30])([CH3:31])[C:28](=[O:33])[CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:15]([C:13]2[CH:12]=[CH:11][C:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[O:7][C:8]=3[CH:14]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:21][C:22]=1[CH3:34]
Reactant: CCOC(=O)c1cc2ccc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)cc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)O)oc2c1
Yield: 95.5 %

Procedure:
6-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-2-carboxylic acid ethyl ester (980 mg, 2.11 mmol) and NaOH (2 N, 10.0 mL) and MeOH (5.0 mL) and THF (5.0 mL) are reacted analogous to Example 2 to give the title compound (880 mg, 96%). MS (ES) m/e: 435.3 (M−1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>C1COCC1>[S:14]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: N#Cc1ccc2cc[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(C#N)cc32)cc1
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a solution of 1H-indole-6-carbonitrile (70 mg, 0.5 mmol, CASRN 15861-36-6) in THF (5 mL) cooled to 0° C. was added with vigorous stirring NaH (25 mg, 60% in oil, 0.65 mmol). After stirring for 30 min, TsCl (140 mg, 0.75 mmol) was added to the mixture. The reaction mixture was stirred at RT for 18 h then partitioned between DCM (300 mL) and water (50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by SiO2 chromatography eluting with a petroleum ether/EtOAc gradient (5 to 10% EtOAc) to afford 100 mg (67%) of 1-tosyl-1H-indole-6-carbonitrile (34) as a white solid: MS (ESI) m/z=297.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]([O:15][CH3:16])=[O:14].[BH4-].[Na+].CO>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(Cl)c(C(=O)OC)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(Cl)cc(CO)cc1Cl
Temperature: 25 °C
Yield: 78.2 %

Procedure:
A solution of dimethyl 2,6-dichlorobenzene-1,4-dicarboxylate (2.3 g, 8.7 mmol) in tetrahydrofuran (10 mL) was treated with sodium borohydride (0.496 g, 13 mmol) and heated to refluxing temperature. The reaction mixture was then treated drop wise with methanol (1 mL) and continued refluxing for about 2 hours. The reaction mixture was warmed to room temperature and quenched with saturated aqueous ammonium chloride solution followed by partitioning with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography using ethyl acetate in hexane (10%) as an eluant to yield methyl 2,6-dichloro-4-(hydroxymethyl)benzoate as a colorless liquid (1.6 g, 80%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3].[Br:12]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.O>C1C=CC=CC=1>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:12])=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3]
Reactant: Cc1ccc(N=[N+]=[N-])c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Solvent: O
Product: [N-]=[N+]=Nc1ccc(CBr)cc1Cl
Yield: 57.6 %

Procedure:
4-Azido-3-chlorotoluene (17.14 g, 0.1 mol) was dissolved in dry benzene (80 ml) and thereto were added N-bromosuccinimide (19.6 g, 0.11 mol) and AIBN (1.64 g, 0.01 mol). The resulting mixture was refluxed in the shade in a nitrogen stream for 10 hr. Water (100 ml) was added and the mixture was filtrated. The aqueous layer of the filtrate was taken and extracted with ether. The organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained brown oil was purified by silica gel column chromatography (eluent; hexane) to give the title compound (14.2 g, yield 58%). m.p.: 75-77° C.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[OH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([OH:20])=[O:19])[NH:15]2)=[CH:11][CH:10]=1>CO>[OH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([O:20][CH3:1])=[O:19])[NH:15]2)=[CH:11][CH:10]=1
Reactant: O=C(O)c1cc2ccc(O)cc2[nH]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1cc2ccc(O)cc2[nH]1
Temperature: 25 °C
Yield: 86 %

Procedure:
A 2M solution of trimethylsilyldiazomethane in hexanes was added to a solution of 6-hydroxy-1H-indole-2-carboxylic acid (0.500 g, 2.82 mmol) in MeOH until the solution remained yellow in color. The solution was stirred at RT until the starting material was consumed as evident by TLC. The reaction mixture was partitioned between water and EtOAc then the organic layer was separated, dried over MgSO4, filtered and concentrated. Purification was accomplished by column chromatography (EtOAc/hexanes) to afford the title compound (0.464 g, 86% yield). 1H NMR (400 MHz, Acetone-d6): δ ppm 10.55 (br. s., 1H), 8.32 (s, 1H), 7.50 (d, 1H), 7.09 (d, 1H), 6.95 (d, 1H), 6.74 (dd, 1H), 3.85 (s, 3H). MS m/z=191.9 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=1)=[O:14].I[C:31]1[S:35][CH:34]=[C:33]([C:36]#[N:37])[CH:32]=1>>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:16]=[CH:17][C:18]([C:31]2[S:35][CH:34]=[C:33]([C:36]#[N:37])[CH:32]=2)=[CH:19][CH:20]=1)=[O:14]
Reactant: N#Cc1csc(I)c1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2cc(C#N)cs2)cc1
Yield: 30 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure A using [2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (351 mg, 0.88 mmol) and 5-Iodo-thiophene-3-carbonitrile (CAS 18800-02-7) (165 mg, 0.88 mmol) to give 100 mg (30% yield). MS (ES+) 380.2 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7](C)[CH:8]1CCN(C2C=CC([N+]([O-])=O)=CN=2)CC1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNC(=O)OC(C)(C)C
Yield: 226.9 %

Procedure:
A solution of methyl (5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-carbamic acid tert-butyl ester (1.4 g, 4.2 mmol) in ethyl acetate (5 mL) in the presence of 10% palladium on carbon (0.15 g) was shaken under 40 psi of hydrogen at room temperature for 2 h. The reaction mixture was filtered through a plug of celite and the filtration pad was washed with ethyl acetate. The combined washings were concentrated and dried to give 5′-amino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methyl-carbamic acid tert-butyl ester (1.25 g, 98%) as a brown solid. This material was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([N:25]([CH3:27])[CH3:26])=[O:24]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:29]1[CH:30]=[CH:20][CH:21]=[C:22]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:28]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CN(C)C(=O)c1cccc(Br)c1
Product: CN(C)C(=O)c1cccc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-N,N-dimethylbenzamide (Intermediate 180), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.