Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C[Mg]Br.N1C=CC=CC=1S[C:16]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)=[O:17].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1COCC1.C(OCC)(=O)C>[CH3:25][O:24][C:22]([C:21]1[CH:26]=[CH:27][C:18]([C:16]([C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)=[O:17])=[CH:19][CH:20]=1)=[O:23]
Reactant: COC(=O)c1ccc(C(=O)Sc2ccccn2)cc1
Reactant: c1cc[nH]c1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)c2ccc[nH]2)cc1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a solution of pyrrole (1.68 g) in toluene (40 mL) was added dropwise methyl magnesium bromide in THF (0.93N solution, 27.8 mL) at −20 to −30° C. After the addition, the reaction solution was further stirred for 30 minutes. A solution of methyl 4-[(2-pyridylsulfanyl)-carbonyl]benzoate (8.33 mmol) in toluene (80 mL) was cooled to −78° C., and thereto was added dropwise the above toluene solution via a cannula in such a manner that the temperature of the reaction mixture was not raised over −65° C. After the addition, the reaction solution was stirred at −78° C. for 2 hours, and thereto was added a saturated aqueous ammonium chloride solution (50 mL), and the mixture was warmed to room temperature. To the reaction solution was added ethyl acetate (100 mL), and the organic layer was separated. Further, the aqueous layer was extracted with ethyl acetate (50 mL×2). The organic layers were combined, and washed successively with 9% hydrochloric acid (100 mL), 10% aqueous sodium hydrogen carbonate solution (100 mL), water (100 mL) and a saturated brine (100 mL), dried over magnesium sulfate, filterd and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1→4/1) to give the title compound (1.40 g) as colorless solid.
Reaction SMILES: [C:1]([N:4]1[C:8]2([CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:7][CH2:6][CH:5]1[C:14]([O:16]CC)=[O:15])(=[O:3])[CH3:2].O.[OH-].[Li+].Cl>C1COCC1.O.CO>[C:1]([N:4]1[C:8]2([CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:7][CH2:6][CH:5]1[C:14]([OH:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1CCC2(CCOCC2)N1C(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)N1C(C(=O)O)CCC12CCOCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.2 %

Procedure:
To a solution of ethyl 1-acetyl-8-oxa-1-azaspiro[4.5]decane-2-carboxylate (170) (93 mg, 0.34 mmol) in THF/water/methanol (1.1 mL/0.6 mL/0.6 mL) was added lithium hydroxide monohydrate (29 mg, 0.69 mmol) and the reaction stirred at room temperature for 3 h. The reaction is treated with 1N HCl (0.7 mL) and partitioned between EtOAc and 0.1 N HCl, the aqueous layer was extracted twice with EtOAc, the combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound as a white solid (79 mg, 95% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:3][O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6].[CH:21]1(C(OC)=O)[CH2:26]CCC[CH2:22]1>>[CH2:16]([C:2]1([CH2:3][O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:10])([CH3:11])[CH3:12])=[O:6])[CH2:20][CH2:26][CH2:21][CH2:22][CH2:1]1)[CH2:17][CH:18]=[CH2:19]
Reactant: COC(=O)C1CCCCC1
Reactant: C=CCCC(C)(C)COC(=O)N[C@H](C(=O)O)C(C)(C)C
Product: C=CCCC1(COC(=O)N[C@H](C(=O)O)C(C)(C)C)CCCCC1

Procedure:
N-{[(1-But-3-en-1-ylcyclohexyl)methoxy]carbonyl}-3-methyl-L-valine was prepared according to the procedure for N-{[(2,2-dimethylhex-5-enyl)oxy]carbonyl}-3-methyl-L-valine by using methyl cyclohexanecarboxylate instead of ethyl isobutyrate in Step 1. LRMS (ESI) m/z 326.3 [(M+H)+; calcd for C18H32NO4: 326.2].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[O:22])[CH:17](OC)[C:16]1=C=O)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[OH-:39].[Na+].Cl.[CH3:42][OH:43]>>[C:42]([CH:17]1[CH2:16][N:15]([S:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH:8]=2)(=[O:14])=[O:13])[CH2:20][CH2:19][N:18]1[C:21]([CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)=[O:22])([OH:43])=[O:39]
Reactant: [OH-]
Reactant: CO
Reactant: COC1C(=C=O)N(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1
Agent: Cl
Agent: [Na+]
Product: O=C(O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1

Procedure:
A mixture of 4-(6-chloronaphth-2-ylsulphonyl)-2-methoxy-carbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine (0.362 g), 1N aqueous sodium hydroxide solution (1.3 ml) and methanol (5 ml) was stirred and heated to reflux for 30 minutes. The mixture was acidified by the addition of 2N aqueous hydrochloric acid (2 ml) and evaporated. The residue was dried to give 2-carboxy-4-(6-chloronaphth-2-ylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine (0.41 g);
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:9]2)[N:5]=[CH:4][N:3]=1.B([C:24]1[CH:35]=[CH:34][C:27]([CH2:28][C@@H:29]([C:31]([OH:33])=[O:32])[NH2:30])=[CH:26][CH:25]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[NH2:30][CH:29]([CH2:28][C:27]1[CH:34]=[CH:35][C:24]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH2:11][CH:10]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)[CH2:9]3)[N:5]=[CH:4][N:3]=2)=[CH:25][CH:26]=1)[C:31]([OH:33])=[O:32]
Reactant: Clc1ccc(C2CCCN(c3ncnc(Cl)n3)C2)cc1
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NC(Cc1ccc(-c2ncnc(N3CCCC(c4ccc(Cl)cc4)C3)n2)cc1)C(=O)O
Temperature: 150 °C
Yield: 5.8 %

Procedure:
A microwave vial was charged with 2-chloro-4-[3-(4-chlorophenyl)-piperidin-1-yl]-[1, 3, 5]triazine (62 mg, 0.2 mmol), 4-borono-L-phenylalanine (60 mg, 0.3 mmol), 1 ml of acetonitrile, and 0.7 ml of water. Aqueous sodium carbonate (0.6 ml; 1M) was added to the solution, followed by 5 mol percent dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, was then purified by Prep-LC to give 5.1 mg of 2-amino-3-(4-{4-[3-(4-chlorophenyl)-piperidin-1-yl]-[1,3,5]triazin-2-yl}-phenyl)-propionic acid. 1H NMR (400 MHz, CD3Cl) δ 8.58 (d, 2H), 8.05 (d, 2H), 7.47 (m, 5 H), 4.96 (m, 1 H), 4.23 (m, 2H), 3.21-3.44 (m, 4 H), 2.37 (m, 5H).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])(=O)=O.[Cl:20]C1C=C2C(=CC=1)NC=C2CC(N)(C)C.C1(C(C2C=CC=CC=2)[O:42][C:43]2[CH:51]=[C:50]3[C:46]([C:47]([CH2:52][C:53]([NH2:56])([CH3:55])[CH3:54])=[CH:48][NH:49]3)=[CH:45][CH:44]=2)C=CC=CC=1>>[ClH:20].[OH:42][C:43]1[CH:51]=[C:50]2[C:46]([C:47]([CH2:52][C:53]([NH:56][CH2:6][CH2:7][O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH2:16][CH:17]([CH3:18])[CH3:19])([CH3:54])[CH3:55])=[CH:48][NH:49]2)=[CH:45][CH:44]=1
Reactant: CC(C)(N)Cc1c[nH]c2cc(OC(c3ccccc3)c3ccccc3)ccc12
Reactant: CC(C)COc1ccccc1OCCOS(C)(=O)=O
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Cl)cc12
Product: CC(C)COc1ccccc1OCCNC(C)(C)Cc1c[nH]c2cc(O)ccc12
Product: Cl

Procedure:
Proceeding as in Example 3, but replacing 2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate with 2-[2-(2-methylprop-1-yloxy)phenoxy]ethyl methanesulfonate and [2-(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]amine with [2-(6-diphenylmethyloxy-1H-indol-3-yl)-1,1-dimethylethyl]amine and then removing the protective group, gave [2-(6-hydroxy-1H-indol-3-yl)-1,1-dimethylethyl]{2-[2-(2-methylprop-1-yloxy)phenoxy]ethyl}amine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([N+:22]([O-])=O)[CH:5]=1.[H][H]>C(OCC)(=O)C.[Ni]>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([NH2:22])[CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccc(C)cc2)c(S(N)(=O)=O)c1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)c(Oc2ccc(C)cc2)c(S(N)(=O)=O)c1

Procedure:
45 g of 3-nitro-4-(4'-methylphenoxy)-5-sulphamoylbenzoic acid methyl ester are suspended in 150 ml of ethyl acetate and hydrogenated for 5 hours with Raney nickel at 50° C. and a hydrogen pressure of 100 atmospheres gauge. After cooling, the Raney nickel is separated and the solution is concentrated to dryness. The 3-amino-4-(4'-methylphenoxy)-4-sulphamoylbenzoic acid methyl ester is recrystallised from mthanol/H2O. Crystals melting at 183°-185° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:16]2[C:7]([C:8]3[CH:9]=[C:10]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:11]([C:17]4[CH:22]=[CH:21][C:20]([C:23]5([NH:27]C(=O)OC(C)(C)C)[CH2:26][CH2:25][CH2:24]5)=[CH:19][CH:18]=4)=[N:12][C:13]=3[CH:14]=[CH:15]2)=[N:6][N:5]=1)[CH3:2].[ClH:41].CCOC(C)=O>CO.C(Cl)Cl>[ClH:41].[ClH:41].[CH2:1]([NH:3][C:4]1[N:16]2[C:7]([C:8]3[CH:9]=[C:10]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:11]([C:17]4[CH:18]=[CH:19][C:20]([C:23]5([NH2:27])[CH2:24][CH2:25][CH2:26]5)=[CH:21][CH:22]=4)=[N:12][C:13]=3[CH:14]=[CH:15]2)=[N:6][N:5]=1)[CH3:2]
Reactant: CCNc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)nc3ccn12
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCNc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5(N)CCC5)cc4)nc3ccn12
Temperature: 25 °C

Procedure:
To a solution of 3-1 (108 mg, 0.202 mmol) in MeOH (2 mL) and DCM (5 mL) was added a 4N solution of HCl in EtOAc (5 mL, 20 mmol). The capped reaction mixture was permitted to stir at room temperature. After 4 hours the reaction mixture was concentrated in vacuo to give 1-{4-[3-(ethylamino)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanamine dihydrochloride (3-2) as a yellow solid. HRMS (M+H)+: observed=435.2302, calculated=435.2292.
Reaction SMILES: C[S-].[Na+].[CH3:4][C:5]([C:8]1[CH:13]=[C:12](/[CH:14]=[CH:15]/[C:16]2[S:17][C:18]([S:21]C)=[N:19][N:20]=2)[CH:11]=[C:10]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:9]=1[OH:27])([CH3:7])[CH3:6].[OH-].[Na+]>CN(C)C=O.O>[CH3:26][C:23]([C:10]1[CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]2[S:17][C:18](=[S:21])[NH:19][N:20]=2)[CH:13]=[C:8]([C:5]([CH3:4])([CH3:6])[CH3:7])[C:9]=1[OH:27])([CH3:24])[CH3:25]
Reactant: CSc1nnc(/C=C/c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Agent: C[S-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(/C=C/c2n[nH]c(=S)s2)cc(C(C)(C)C)c1O
Temperature: 75 °C
Yield: 56.4 %

Procedure:
Sodium thiomethoxide (0.5 g, 0.007 mole) is added to a solution of (E)-2,6-bis(1,1-dimethylethyl)-4-[2-[5-(methylthio)-1,3,4-thiadiazol-2-yl]ethenyl]-phenol (1.0 g, 0.0028 mole) in dimethylformamide (10 ml). The resulting mixture is heated to 75° C. for two hours. The solution is cooled and diluted with water (20 ml). The mixture is treated with 1M NaOH (6 ml) and the aqueous solution is washed with ether (2×). The aqueous layer is made acidic by the addition of cold 6 M HCl (3 ml) and the product is then extracted with a 1:1 ethyl acetate/diethyl ether mixture (2×). The combined organic layers are washed with brine and dried over MgSO4. Filtration and concentration in vacuo, followed by recrystallization from ethyl acetate/hexane gives 0.55 g of (E)-5-[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenyl]-1,3,4-thiadiazol-2-(3H)-thione. (0.98 g theor., 57%), mp 248°-249° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([N:20]3[CH2:28][C:27]4[C:22](=[C:23]([NH:29][CH2:30][C:31]5[CH:32]=[C:33]6[C:38](=[CH:39][CH:40]=5)[N:37]=[CH:36][CH:35]=[CH:34]6)[CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:41])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([N:20]3[CH2:28][C:27]4[C:22](=[C:23]([NH:29][CH2:30][C:31]5[CH:32]=[C:33]6[C:38](=[CH:39][CH:40]=5)[N:37]=[CH:36][CH:35]=[CH:34]6)[CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:41])=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N3Cc4cccc(NCc5ccc6ncccc6c5)c4C3=O)ccc2C(C)(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCc2cc(N3Cc4cccc(NCc5ccc6ncccc6c5)c4C3=O)ccc21

Procedure:
The title compound was prepared by treatment of 4,4-dimethyl-7-{1-oxo-7-[(quinolin-6-ylmethyl)-amino]-1,3-dihydro-isoindol-2-yl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (Example 3) with TFA in CH2Cl2. MS (m/z)=449.0 (M+H)+ Calc'd for C29H28N4O: 448.5.
Reaction SMILES: O.[OH-].[Na+].[CH3:4][CH:5]([CH3:29])[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:18][C:19](=O)[CH2:20][CH2:21][C:22]1([CH3:27])[O:26][CH2:25][CH2:24][O:23]1>C(O)C>[CH3:4][CH:5]([CH3:29])[CH2:6][N:7]1[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=[C:19]1[CH2:20][CH2:21][C:22]1([CH3:27])[O:26][CH2:25][CH2:24][O:23]1
Reactant: CC(C)CNc1c(NC(=O)CCC2(C)OCCO2)cnc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Cn1c(CCC2(C)OCCO2)nc2cnc3ccccc3c21
Temperature: 25 °C
Yield: 95 %

Procedure:
Water (3 mL) followed by solid sodium hydroxide (0.4 g, 10.7 mmol) were added to a stirred solution of N-{4-[(2-methylpropyl)amino]quinolin-3-yl}-3-(2-methyl-1,3-dioxolan-2-yl)propanamide (2.55 g, 7.13 mmol) in ethanol (10 mL). The reaction mixture was heated at reflux for 30 minutes, then was allowed to cool to room temperature and was concentrated under reduced pressure. The resulting aqueous slurry was diluted with water (50 mL) and was extracted with dichloromethane (2×50 mL). The organic layers were combined, washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield 2.3 g of crude 1-(2-methylpropyl)-2-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-1H-imidazo[4,5-c]quinoline as a clear oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:17])[CH2:8][O:7][C:6]2([O:13][CH2:12][C:11]([CH2:15][OH:16])([CH3:14])[CH2:10][O:9]2)[O:5][CH2:4]1.N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].[CH3:31][CH2:32][O:33]C(C)=O>>[C:24]([O:16][CH2:15][C:11]1([CH3:14])[CH2:10][O:9][C:6]2([O:5][CH2:4][C:3]([CH2:2][O:1][C:32](=[O:33])[CH3:31])([CH3:17])[CH2:8][O:7]2)[O:13][CH2:12]1)(=[O:26])[CH3:25]
Reactant: CC1(CO)COC2(OC1)OCC(C)(CO)CO2
Reactant: CCOC(C)=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC1(C)COC2(OC1)OCC(C)(COC(C)=O)CO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 100 mL one-neck round-bottom flask was charged with 3,9-dihydroxymethyl-3,9-dimethyl-1,5,7,11-tetraoxaspiro[5.5]undecane prepared as in Example 2 (DHMDM-SOC, 4.6 g, 0.0185 mol) and pyridine (25 mL) under N2. After DHMDM-SOC was dissolved, acetic anhydride (26.2 mL, 0.28 mole) was added. The mixture was stirred at room temperature for 4 h. TLC (1:3 Hexanes:EtOAc) revealed the disappearance of DHMDM-SOC and a new product spot (Rf~0.6). Pyridine and unreacted acetic anhydride were removed under reduced pressure using rotary evaporator. The residue was off-white solid as crude product. It was purified by recrystallization from cyclohexane. The solid was dissolved in ~300 mL of cyclohexane, and the solution was cooled to room temperature, kept in refrigerator overnight to crystallize. The crystals were collected by filtration, washed with cyclohexane (3×20 mL), and dried in vacuo, giving 5.7 g of white crystals as product (93.4 % of theory). m.p. (DSC): 137.4° C.; 1H NMR (CDCl3, 75 Mhz) δ0.87 (s, 6H), 2.05 (s, 6H); 3.65-3.80 (m, 8H), 4.12 (s, 4H); 13C NMR (CDCl3, 75 MHz) δ1711, 20.73, 32.88, 66.17, 67.87, 68.26, 114,20, 170.78. Anal. calcd. for C15H24O8 ; C, 54.21; H, 7.28. Found: C, 54.31; H, 7.48.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([CH3:10])([CH3:9])[C:5](Cl)([CH3:7])[CH3:6].[OH-:12].[K+].[OH2:14]>O1CCOCC1>[CH3:9][C:4]1([CH3:10])[C:5]([CH3:7])([CH3:6])[CH:3]1[C:2]([OH:14])=[O:12]
Reactant: CC(C)(Cl)C(C)(C)C(=O)CBr
Reactant: O
Reactant: [OH-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1(C)C(C(=O)O)C1(C)C
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A solution of 4.1 g of 1-bromo-4-chloro-3,3,4-trimethyl-2-pentanone in 10 ml of 1,4-dioxane was added dropwise at 30° C to a solution comprising 3.3 g of potassium hydroxide, 30 ml of water and 20 ml of dioxane, and the resulting solution was stirred at 20° C for 15 hours. Thereafter, the reaction solution was worked up in the same manner as in Example 1 to obtain 1.8 g of the desired 2,2,3,3-tetramethylcyclopropane-1-carboxylic acid as a white crystal (yield, 76%).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[N:16][CH:17]=3)[CH:10]=2)[N:5](C2CCCCO2)[N:4]=1)=O.[S].[F:32][C:33]1[CH:34]=[C:35]([C:39]2[C:40]([NH2:46])=[C:41]([NH2:45])[CH:42]=[N:43][CH:44]=2)[CH:36]=[CH:37][CH:38]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(O)CCC>[F:32][C:33]1[CH:34]=[C:35]([C:39]2[C:40]3[N:46]=[C:1]([C:3]4[C:11]5[C:6](=[N:7][CH:8]=[C:9]([C:12]6[CH:13]=[C:14]([NH:18][C:19](=[O:24])[C:20]([CH3:22])([CH3:21])[CH3:23])[CH:15]=[N:16][CH:17]=6)[CH:10]=5)[NH:5][N:4]=4)[NH:45][C:41]=3[CH:42]=[N:43][CH:44]=2)[CH:36]=[CH:37][CH:38]=1
Reactant: Nc1cncc(-c2cccc(F)c2)c1N
Reactant: CC(C)(C)C(=O)Nc1cncc(-c2cnc3c(c2)c(C=O)nn3C2CCCCO2)c1
Agent: CC[SiH](CC)CC
Agent: [S]
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: CC(C)(C)C(=O)Nc1cncc(-c2cnc3[nH]nc(-c4nc5c(-c6cccc(F)c6)cncc5[nH]4)c3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
A solution of N-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)pivalamide (LXV) (75 mg, 0.18 mmol), sulfur (64 mg, 0.20 mmol) and 5-(3-fluorophenyl)pyridine-3,4-diamine (XL) (41 mg, 0.20 mmol) in n-butanol (10 mL) was refluxed overnight under argon. The solution was cooled and filtered and dried under vacuum for 1 h. The residue was taken in dry DCM (5 mL). Triethylsilane (72 μL, 0.45 mmol) followed by TFA (2.5 mL) was added to the solution and stirred for 2 h at room temperature. The solvent was removed under vacuum. Water was added to the residue, sonicated briefly and basified with a 5N NH4OH solution. The solids formed were filtered, washed with cold water and dried at room temperature. The solids were boiled in DCM, cooled to room temperature and sonicated briefly. The solids were filtered, washed with DCM and dried under vacuum to give N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)pivalamide (2) as a brown solid (66 mg, 0.13 mmol, 72% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.30 (s, 9H), 7.22 (t, 1H), 7.57-7.66 (m, 1H), 8.25 (d, 1H), 8.36 (d, 1H), 8.55 (s, 1H), 8.74 (s, 1H), 8.78 (s, 1H), 8.89 (s, 1H), 8.97 (s, 1H), 9.04 (s, 1H), 9.07 (s, 1H), 9.61 (s, 1H), 13.92 (brs, 1H), 14.63 (brs, 1H); ESIMS found C28H23FN8O m/z 507.5 (M+H).
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH2:4]([O:6][C:7](=[O:21])[C:8](=O)[CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)[CH3:5]>COCCO>[CH2:4]([O:6][C:7]([C:8]1[C:18]2=[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]2)[CH2:13][CH2:12][CH2:11][N:10]3[CH:9]=1)=[O:21])[CH3:5]
Reactant: CCOC(=O)C(=O)CN1CCCc2ccccc21
Agent: [Cl-]
Agent: [Mg+2]
Solvent: COCCO
Product: CCOC(=O)c1cn2c3c(cccc13)CCC2
Temperature: 125 °C
Reaction time: 0.25 h
Yield: 43.6 %

Procedure:
Anhydrous magnesium chloride (29.4 g, 0.31 mol) was suspended in 2-methoxyethanol (400 ml), and the mixture was stirred for 15 minutes at 125° C. A solution of 3-(3,4-dihydro-2H-quinolin-1-yl)-2-oxopropionic acid ethyl ester (76.57 g 0.31 mol) in 2-methoxyethanol (100 ml) was then added and the mixture stirred at 125° C. for 60 minutes. The mixture was stirred for a further 5 hours at reflux, cooled and evaporated to dryness. The residue was then acidified with 2 M hydrochloric acid (500 ml) and extracted with dichloromethane (3×500 ml). The combined organic layers were then washed with 5% sodium bicarbonate solution and dried over anhydrous magnesium sulfate before being evaporated to dryness. The residue was then purified on a silica gel chromatography column, eluting with ethyl acetate/hexanes (1:4) to provide 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid ethyl ester (31.0 g, 47%). 1H NMR (CDCl3) 400 MHz δ: 7.9(d, 1H, J=8 Hz), 7.79(s, 1H), 7.17(m, 1H), 6.99(d, 1H, J=7.2 Hz), 4.37(m, 2H), 4.18(t, 2H, J=5.6 Hz), 3.0(t, 2H, J=6 Hz), 2.24(t, 2H, J=6 Hz), 1.42(t, 3H, J=7.2 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10])#[CH:2].I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18]>>[CH3:10][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]1[O:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:2]=1
Reactant: C#Cc1ccccc1OC
Reactant: Oc1ccccc1I
Product: COc1ccccc1-c1cc2ccccc2o1

Procedure:
The general procedure was used to convert 2-ethynyl-anisole and 2-iodophenol to the title product. Purification by flash chromatography (10% ethyl acetate in hexanes as the eluent) gave the analytically pure product as a white solid (348 mg, 77% yield). 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=7.73, 1H), 7.58 (d, J=6.41, 1H), 7.48 (d, J=8.10, 1H), 7.34 (s, 1H), 7.26-7.18 (m, 3H), 7.03 (t, 1H), 6.89 (d, J=8.29, 1H), 3.86 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 156.42, 153.83, 152.15, 129.77, 129.20, 126.95, 124.08, 122.62, 121.01, 120.69, 119.25, 110.93, 110.78, 106.31, 55.87. Anal. Calcd. for C15H12O2: C, 80.34; H, 5.39. Found C, 80.60; H, 5.65. m.p.: 76° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][CH2:20]O)=[CH:16][N:15]([CH2:22][C:23]3[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[CH:43]([NH:46][CH:47]([CH3:49])[CH3:48])([CH3:45])[CH3:44]>C(Cl)Cl.CCN(CC)CC>[Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][CH2:20][N:46]([CH:47]([CH3:49])[CH3:48])[CH:43]([CH3:45])[CH3:44])=[CH:16][N:15]([CH2:22][C:23]3[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1
Reactant: COc1c(C)cnc(Cn2cc(C#CCO)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Reactant: CC(C)NC(C)C
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)cnc(Cn2cc(C#CCN(C(C)C)C(C)C)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Reaction time: 72 h

Procedure:
A solution of N-[4-chloro-5-(3-hydroxy-prop-1-ynyl)-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide (9.0 g, 19.7 mmol) and Et3N (2 mL) in DCM (50 mL) was treated with MsCl (15.3 mL, 19.7 mmol) at 0° C. for 20 min and evaporated to give a yellow solid, containing mostly the desired mesylate (10.7 g). An aliquot of this solid (106.8 mg, 0.2 mmol) was treated with diisopropylamine (20.3 mg, 28.1 μL) in DCM (2 mL) at 0° C. for 10 h, and then at 25° C. for 3 days. Evaporation and preparative plate chromatography gave the title compound.