Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].Cl[C:9]1[C:22]2[C:13](=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[N:15]3)[N:12]=[C:11]([CH3:23])[CH:10]=1>C1COCC1>[CH3:3][O:4][CH2:5][CH2:6][O:7][C:9]1[C:22]2[C:13](=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[N:15]3)[N:12]=[C:11]([CH3:23])[CH:10]=1
Reactant: COCCO
Reactant: Cc1cc(Cl)c2ccc3cccnc3c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1cc(C)nc2c1ccc1cccnc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.6 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 1.75 g, 43.7 mmol) in THF (30 mL) a solution of 2-methoxyethanol (3.30 g, 43.7 mmol) in anhydrous THF (10 mL) was slowly added. The mixture was stirred at room temperature for 20 minutes and a solution of 4-chloro-2-methyl-[1,10]phenanthroline (2.00 g, 8.8 mmol) in anhydrous THF (20 mL) was added. The reaction mixture was refluxed for 18 hours and the solvent was removed in a rotary evaporator. The residue was treated with methylene choride (100 mL) and saturated NaHCO3 (100 mL) and transferred to a separatory funnel. The organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was washed with hexane and purified by flash chromatography (SiO2, MeOH/DCM, 1:30) to afford the pure product as a light yellow solid (1.17 g, 50%).
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[N:16]=2)[CH:12]=[N:11]1)[CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)#[N:2].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:5]1([CH:4]([N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([N:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)=[O:27])=[CH:29][CH:30]=4)[N:16]=3)[CH:12]=[N:11]2)[CH2:3][C:1]#[N:2])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: N#CCC(C1CCCC1)n1cc(-c2ccnc(Nc3ccc(C(=O)O)cc3)n2)cn1
Reactant: CN1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2ccc(Nc3nccc(-c4cnn(C(CC#N)C5CCCC5)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)benzoic acid (30 mg, 0.07 mmol), 1-methyl-piperazine (8.3 μL, 0.074 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.4 mg, 0.089 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (31 μL, 0.18 mmol). The reaction was stirred at room temperature for 1 h, quenched with water, purified on HPLC to give the desired product as a racemic mixture (28 mg, 82%). LCMS (M+H) 485.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[NH:11][C:12]1[C:21]2[CH:22]=[CH:23][N:24]=[C:25]([O:26]C)[C:20]=2[C:19]2[C:14](=[CH:15][CH:16]=[N:17][CH:18]=2)[N:13]=1.[Si]([N:32]=[N+:33]=[N-:34])(C)(C)C.C(Cl)(Cl)Cl.B(Br)(Br)Br>C(OCC)(=O)C>[Cl:10][C:4]1[CH:5]=[C:6]([C:8]2[N:32]=[N:33][NH:34][CH:9]=2)[CH:7]=[C:2]([Cl:1])[C:3]=1[NH:11][C:12]1[C:21]2[CH:22]=[CH:23][NH:24][C:25](=[O:26])[C:20]=2[C:19]2[C:14](=[CH:15][CH:16]=[N:17][CH:18]=2)[N:13]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1cc(Cl)c(Nc2nc3ccncc3c3c(OC)nccc23)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=c1[nH]ccc2c(Nc3c(Cl)cc(-c4c[nH]nn4)cc3Cl)nc3ccncc3c12
Temperature: 150 °C

Procedure:
N-(2,6-Dichloro-4-ethynylphenyl)-10-methoxypyrido[4,3-c]-1,6-naphthyridin-6-amine (66 mg, 0.167 mmol) and TMS-N3 (1.5 mL, 11.30 mmol) were combined and heated in a sealed tube to 150° C. for 16 h. Volatiles were evaporated under vacuum. To the residue was added chloroform (1 mL) and boron tribromide (1.2 mL, 1.2 mmol, 1M in dichloromethane) and the mixture was heated at 85° C. for 45 min in a sealed tube. After cooling to room temperature, the reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, followed by brine. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in THF/MeOH, filtered and purified by reverse phase HPLC to afford the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.C([N:32]=[C:33]=[S:34])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>C(Cl)Cl>[NH2:32][C:33]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)=[S:34]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
tert-Butyl piperidin-4-ylcarbamate (5.5 g) was dissolved in anhydrous DCM (75 ml). H-Fluoren-9-ylmethyl isothiocyanatidocarbonate (Fmoc isothiocyanate; 7.75 g) was added in small portions at room temperature after which time a white precipitate formed. The mixture was stirred at room temperature for 90 min. The solvent was removed in vacuo and the crude mixture was treated with 10% piperidine in MeOH (100 ml) for 12 h. The mixture was concentrated in vacuo and triturated with n-hexanes. The white crystalline material was filtered and washed well with n-hexanes and dried in vacuo to afford the title compound (6.55 g).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl[C:17]([O:19][CH3:20])=[O:18].O>O1CCCC1>[F:9][C:10]1[C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: COC(=O)Cl
Reactant: Fc1ccccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccnc1F
Temperature: -78 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
2 M lithium diisopropyl amide (11.3 mL, 22.5 mmol) is slowly added over a solution of 2-fluoropyridine (2 g, 20.5 mmol) in tetrahydrofuran (90 mL) under nitrogen atmosphere at −78° C. After 4 h at that temperature methyl chloroformate (1.9 mL, 24.6 mmol) is added and the mixture is stirred for an additional hour at −78° C. and allowed to reach room temperature overnight. Reaction mixture is slowly poured over water and extracted in diethyl ether. Organic layer is washed with brine, dried over sodium sulfate and solvent is evaporated in vacuo. Residue is purified by normal phase Isco chromatography eluting with hexane/diethyl ether (9/1) to give 495.2 mg of the title compound. MS (m/z): 156 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=O)[C:4]=2[CH:3]=[CH:2]1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C:12]1=[O:20]>CN(C)C=O.O>[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[NH:1][CH:2]=[CH:3][C:4]2=3)[C:12]1=[O:20]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C1CCCc2[nH]ccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C1=C1CCCc2[nH]ccc21
Temperature: 140 °C
Yield: 11.9 %

Procedure:
A mixture of 680 mg 1,5,6,7-tetrahydro-4H-indol-4-one and 1.33 g oxindole in 3 ml dimethylforamide was heated at 140° C. for 50 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with water and then brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified on a silica gel column using hexanes/ethyl acetate as the eluent to provide 150 mg of 1′,5′,6′,7′-tetrahydro-1H-[3,4′]biindolyliden-2-one as a yellow solid.
Reaction SMILES: S(=O)(=O)(O)O.O.[C:7]([C@:9]1([OH:31])[C:14](=[CH2:15])[CH2:13][C@H:12]2[C@H:16]3[C@H:26]([CH2:27][CH2:28][C@:10]12[CH3:11])[C@:24]1([CH3:25])[C:19](=[CH:20][C:21](=[O:29])[CH2:22][CH2:23]1)[C:18](=[CH2:30])[CH2:17]3)#[CH:8].C1C[O:35]CC1.C(=O)([O-])[O-].[Na+].[Na+]>O.CO>[C:7]([C@:9]1([OH:31])[C:14](=[CH2:15])[CH2:13][C@H:12]2[C@H:16]3[C@H:26]([CH2:27][CH2:28][C@:10]12[CH3:11])[C@:24]1([CH3:25])[C:19](=[CH:20][C:21](=[O:29])[CH2:22][CH2:23]1)[C:18](=[CH2:30])[CH2:17]3)(=[O:35])[CH3:8]
Reactant: C1CCOC1
Reactant: C#C[C@]1(O)C(=C)C[C@H]2[C@@H]3CC(=C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC(=C)[C@@]3(O)C(C)=O)[C@@]2(C)CCC(=O)C=C12
Reaction time: 8 h

Procedure:
Mercuric oxide red (0.32 g) was mixed with sulfuric acid/water (sulfuric acid, 0.4 ml; water, 6.0 ml) and let stand overnight. 17α-Ethynyl-17β-hydroxy-6,16-dimethyleneandrosta-4-en-3-one (Example 6, 5.0 g) is mixed with THF (15 ml). The mercuric sulfate solution is added the reaction heated to 41°-49° over a period of 6 hrs at which time TLC indicates the reaction is completed. Sodium carbonate (0.79 g) in water (10 ml) is added and the mixture stirred for 5 min. Celite (5 g) is added and the mixture stirred 1/2 hr at 20°-25°. The mixture is filtered through Celite (5 g), the solids washed with methanol/THF; 1/1 (2×10 ml) and once with THF (10 ml), followed by methylene chloride (10 ml). The filtrate and washings are concentrated under reduced pressure to about 35 ml, at which point crystals begin forming. Methanol (50 ml) is added and the mixture again concentrated under reduced pressure and permitted to sit overnight at 20°-25° under nitrogen atmosphere. Water (500 ml) is added, slowly at first, with stirring over a period of 15 min. The mixture is filtered, the solids washed with water (3×20 ml), and hexane (2×10 ml). The solids were dried under nitrogen to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=1[CH3:1]
Reactant: Cc1ccc(C)c(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)ccc1C
Temperature: 25 °C

Procedure:
In methanol (30 ml), 2,5-dimethylbenzoic acid (1.772 g) was dissolved. The reaction solution was added with concentrated sulfuric acid (0.7 ml) and the whole was refluxed under heating for 17 hours. After having been cooled to room temperature, the reaction solution was concentrated under reduced pressure. The resultant residue was added with a saturated aqueous sodium hydrogen carbonate solution to make the pH thereof to 9, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After a drying agent was filtrated out, the filtrate was concentrated under reduced pressure. The resultant residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (1.9353 g) as a pale-yellow oily substance.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH:14]2[CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25].[CH:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28]>ClCCl>[CH:27]([C:29]1[CH:34]=[C:33]([N:16]2[CH2:15][CH:14]([CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])[C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][CH3:9])[CH:12]=3)[CH2:17]2)[CH:32]=[CH:31][CH:30]=1)=[O:28]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)CNC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(CCNC(C)=O)CN(c1cccc(C=O)c1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Copper acetate Cu(OAc)2 (960 mg; 5 mmol) and triethylamine (1.5 ml; 10.5 mmol) are suspended in 60 ml of dichloromethane. The compound of Example 4 (1 g; 3.5 mmol), 3-formylphenylboronic acid (1.05 g; 7 mmol) and molecular sieve are then added in succession and progressively to the solution. The reaction mixture is stirred at ambient temperature for 2 hours. The mixture is filtered, washed with water, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue obtained is purified by chromatography on silica gel (eluant: dichloromethane with the progressive addition of methanol until the proportions 9/1 are reached) to yield the title product in the form of a yellow oil.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=2[O:29][CH2:30][CH2:31]OS(C)(=O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[N:9]3[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=2[O:29][CH2:30][CH2:31]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc([N+](=O)[O-])c3OCCOS(C)(=O)=O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c-3cccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 97.1 %

Procedure:
To a solution of methyl 3-cyclohexyl-2-[2-(2-methanesulfonyloxyethoxy)-3-nitrophenyl]-1H-indole-6-carboxylate (12.60 g, 24.4 mmol) in N,N-dimethylformamide (190 ml) was added potassium carbonate (5.06 g, 36.6 mmol), and the mixture was stirred at 90° C. for 1.5 hr. The reaction mixture was allowed to iv cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was concentrated under reduced pressure to give methyl 12-cyclohexyl-4-nitro-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (9.96 g, yield 97%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15](=[O:16])[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][NH:12]2)=[N:9][CH:10]=1.C(N(CC)C(C)C)(C)C.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34]([Cl:36])=[O:35]>ClCCl>[ClH:36].[CH3:32][C:33]([CH3:38])([CH3:37])[C:34]([NH:3][CH2:4][C:5]1[CH:10]=[N:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][NH:12]2)=[CH:7][CH:6]=1)=[O:35]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
100 mg (0.3 mmol) of the compound from Example 13 are suspended in 3 ml of dichloromethane. 152 mg (1.2 mmol) of N,N-diisopropylethylamine (Hünig base) are added, and the mixture is stirred at RT for 5 min. 43 mg (0.4 mmol) of 2,2-dimethylpropanoyl chloride are then added, and the mixture is stirred at RT for 16 h. The mixture is then concentrated on a rotary evaporator, the residue is taken up in 5 ml of dioxane and 1 ml 1 N aqueous sodium hydroxide solution is added. This mixture is then purified by preparativer HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA to the water). The product-containing fractions are combined and concentrated on a rotary evaporator. The residue is dissolved in 1 N hydrochloric acid, and the solution is lyophilized. The solid is then stirred in tert-butyl methyl ether for 30 min, filtered off and dried under high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC.[Cl-].[Li+].O>CN(C=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>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([CH:13]=[CH2:14])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(Cl)nc1N
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cnc(C(=O)OC)c(N)n1
Temperature: 85 °C

Procedure:
To a mixture of 3-amino-5-chloro-pyrazine-2-carboxylic acid methyl ester (GB 1248146, 161 mg 0.86 mmol), tributyl(vinyl)tin (0.352 ml, 1.204 mmol) and lithium chloride (102 mg, 2.498 mmol) in DMF (4 ml) was added PdCl2(PPh3)2 (30.2 mg, 0.043 mmol) and the mixture was heated to 85° C. for 2.5 h. After cooling to room temperature water was added and the mixture was extracted with EtOAc, the combined organic layers were washed with water and half saturated aq. NaCl, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 1:9) to provide the title compound as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[NH:23][N:22]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([CH:13]([OH:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[NH:23][N:22]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C(O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a solution of Ethyl 2-(5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophen-2-yl)-2-hydroxyacetate (Compound 191), (100 mg, 0.24 mmol, 1.0 eq) in DMSO (10 mL) was added IBX (168 mg, 0.6 mmol, 2.5 eq). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed (brine), dried (Na2SO4), filtered and concentrated to give a residue, the residue was purified by silica gel column chromatography (PE:EA=2:1) to give ethyl 2-(5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophen-2-yl)-2-oxoacetate (Compound 189) (90 mg, 90.8%). LC-MS (m/z): 418.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.75-0.79 (m, 2H), 0.99-1.01 (m, 2H), 1.35 (t, J=7.0 Hz, 3H), 1.93-1.97 (m, 1H), 4.37-4.42 (m, 2H), 6.43 (s, 1H), 7.89 (d, J=3.6 Hz, 1H), 8.14 (d, J=3.6 Hz, 1H), 8.51 (s, 1H), 9.50 (s, 1H), 12.35 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[C:8]([C:15](OCC)=[O:16])[CH:7]=1.[H-].[Al+3].[H-].[H-].O>O1CCCC1>[NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([CH3:13])[CH3:14])=[C:8]([CH2:15][OH:16])[CH:7]=1
Reactant: CCOC(=O)c1cc(CSCCN)oc1CN(C)C
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1oc(CSCCN)cc1CO
Yield: 62.5 %

Procedure:
A solution of 5-[[2-(amino)ethyl]thio]methyl-2-(dimethylaminomethyl)-3-furancarboxylic acid, ethyl ester (0.75 g) in dry tetrahydrofuran (50 ml) at 0° was treated with a 0.5 molar solution of aluminium hydride in tetrahydrofuran (35 ml). After 2 hours water (6 ml) was added, and the filtered solution evaporated in vacuo. The oily residue was distilled affording the title compound (0.4 g), b.p. 170°/10-1 mm Hg.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=O.[CH:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:13]([N:16]1[CH2:21][CH2:20][N:19]([C:1]([C:4]2[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=2)=[O:3])[CH2:18][CH2:17]1)([CH3:15])[CH3:14]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(C)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc(B(O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-carboxyphenylboronic acid (1 eq, 213 mg) in DMF (5 ml) is treated with 1-isopropylpiperazine (1 eq, 155 mg) and the reaction mixture is stirred at RT for 10 minutes. TEA (1.2 eq, 0.202 ml) and HATU (2.4 eq, 1.104 g) are added and the resulting mixture is stirred at RT overnight. The reaction is quenched by addition of water and the mixture is extracted with DCM (2×). The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is dried in vacuo at 50° C. overnight to afford the title compound which is used without further purification [M+H]+=277
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11]O)=[C:9]([Br:13])[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]=1)=[O:5])[CH3:2].P(Br)(Br)[Br:21]>CCOCC>[Br:13][C:9]1[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:10]=1[CH2:11][Br:21]
Reactant: CCOC(=O)c1nn(-c2ccccc2)c(Br)c1CO
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CCOC(=O)c1nn(-c2ccccc2)c(Br)c1CBr
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a solution of ethyl-5-bromo-4-(hydroxymethyl)-1-phenyl-1H-pyrazole-3-carboxylate (2.91 g, 8.98 mmol, 1 eq) in Et2O cooled at −10° C. is added phosphorus tribromide (1.02 mL, 10.77 mmol, 1.2 eq) and the reaction mixture is stirred at Rt for 1 h. The reaction mixture is poured over ice and extracted with MTBE. The organic layer is washed with brine, dried over Na2SO4 and concentrated to afford 2.1 g (60%) of the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 7.65-7.57 (m, 5H), 4.77 (s, 2H), 4.35 (q, J=6.0 Hz, 2H), 1.32 (t, J=6.6 Hz, 3H). HPLC (max plot) 83.30%; Rt 5.33 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][N:15]([CH3:30])[CH2:16][CH2:17][C:18]1[S:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]=1[C:27](=[O:29])[CH3:28]>C(Cl)Cl.CCCCCC>[CH3:30][N:15]([CH3:14])[CH2:16][CH2:17][C:18]1[S:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]=1[C:27]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)([OH:29])[CH3:28]
Reactant: Fc1ccc(Br)nc1
Reactant: CC(=O)c1c(CCN(C)C)sc2ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: ClCCl
Product: CN(C)CCc1sc2ccccc2c1C(C)(O)c1ccc(F)cn1
Temperature: -78 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
2-Bromo-5-fluoropyridine (5 g, 0.03 mol) was dissolved in methylene chloride (18 mL) and was cooled at −78° C. 1.6 M of n-butyllithium in hexane (18 mL) was added dropwise in 5 minutes and the reaction was stirred for 120 minutes at −78° C. Then a solution of 1-[2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-ethanone (1.75 g, 7.1 mmol) dissolved in methylene chloride (9 mL) and added dropwise and the mixture was allowed to warm to room temperature gradually overnight. The reaction was quenched with aq NH4Cl, followed by water and ammonium hydroxide. The organic layer was extracted with Methylene chloride, and dried over sodium sulfate. Silica gel column chromatography (eluent: 9:1 DCM/MeOH) afforded 1.656 g of 1-[2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-1-(5-fluoro-pyridin-2-yl)-ethanol (Compound 7-1) (68%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].Cl.[CH:15]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][C:17]([NH2:26])([CH2:18][CH2:19]3)[CH2:16]1)[CH2:23]2.N1C=CC=CC=1>O>[CH:15]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][C:17]([NH:26][C:11]([C:2]4[CH:3]=[N:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)=[O:12])([CH2:18][CH2:19]3)[CH2:16]1)[CH2:23]2
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: NC12CCC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC12CCC3CC(CC(C3)C1)C2)c1cnc2ccccc2n1
Yield: 57 %

Procedure:
Prepared from 2-quinoxaloyl chloride (135 mg, 0.70 mmol), tricyclo[4.3.1.1(3,8)]undec-3-ylamine hydrochloride (100 mg, 0.60 mmol), pyridine (5 mL), and water (50 mL) yielding 110 mg (57%) of (168):