Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[P:7](Cl)([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[S:8].[C:16]([C:20]1[S:21][C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][C:24]=1[OH:25])([O:18][CH3:19])=[O:17]>CC(C)=O>[C:16]([C:20]1[S:21][C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][C:24]=1[O:25][P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[S:8])([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1cc(O)c(C(=O)OC)s1
Reactant: CCOP(=S)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOP(=S)(OCC)Oc1cc(C(=O)OC)sc1C(=O)OC
Temperature: 20 °C
Reaction time: 15 h
Yield: 48.9 %

Procedure:
7 g of potassium carbonate and 8.9 g of O,O-diethyl chlorothiophosphate were added to a solution of 10.9 g of 2,5-dicarbomethoxy-3-hydroxy-thiophene in 500 ml of acetone and the mixture was stirred for 15 hours at 20° C. and was then filtered. The filtrate was evaporated to dryness and the residue was empasted with a 10-1 petroleum ether-isopropyl ether mixture. The mixture was vacuum filtered and the precipitate was crystallized from ethanol to obtain 8.5 g of 2,5-dicarbomethoxy-3-(diethoxythiophosphoryloxy)-thiophene melting at 50° C.
Reaction SMILES: C(OC([NH:8][C:9](=[NH:36])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH:17]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]([O:33]CC)=[O:32])[C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=1)=O)(C)(C)C.[Li+].[OH-]>C1COCC1>[C:9]([C:10]1[CH:11]=[CH:12][C:13]([NH:16][CH:17]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]([OH:33])=[O:32])[C:18]([OH:20])=[O:19])=[CH:14][CH:15]=1)(=[NH:8])[NH2:36]
Reactant: CCOC(=O)COc1ccccc1C(Nc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N=C(N)c1ccc(NC(C(=O)O)c2ccccc2OCC(=O)O)cc1
Reaction time: 4 h
Yield: 53.1 %

Procedure:
499 mg of ethyl (RS)-[4-(tert-butoxycarbonylamino-imino-methyl)-phenylamino]-(2-ethoxycarbonylmethoxy-phenyl)-acetate were treated in 14 ml of THF with 2 ml of 1N LiOH, adjusted to pH 4 after 4 hrs. with 2 ml of 1N HCl and evaporated in a vacuum. From acetonitrile-water there were obtained 182 mg of (RS)-(4-carbamimidoyl-phenylamino)-(2-carboxymethoxy-phenyl)-acetic acid, m.p. 223° C., MS: 344 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:4]2[N:3]=1.CC1(C)C(C)(C)OB([C:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH:47]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.O1CCOCC1>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:4]2[N:3]=[C:2]([C:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH:47]=2)[CH:7]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 96860.5 %

Procedure:
To a 40 mL scintillation vial was charged 5-chloro-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)-ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.86 mmol, 480 mg), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.30 mmol, 400 mg), K3PO4 (2.60 mmol, 550 mg), and PdCl2(dppf).CH2Cl2 (0.086 mmol, 70 mg). To this reaction mixture was added a 9:1 solution of 1,4-dioxane:H2O (10 mL). The vial was flushed with argon, sealed with Teflon tape, and stirred at 100° C. 18 hours. After 18 hours, the reaction was concentrated in vacuo and the residue purified via silica gel chromatography to yield tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (586 mg, 833 mmol, 97% yield) as yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([CH2:12][CH2:13][CH3:14])[C:10]=1I)=[O:5])[CH3:2].[Cu](C#N)[C:16]#[N:17]>[C-]#N.C([N+](CC)(CC)CC)C.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([CH2:12][CH2:13][CH3:14])[C:10]=1[C:16]#[N:17])=[O:5])[CH3:2]
Reactant: CCCc1n[nH]c(C(=O)OCC)c1I
Reactant: N#C[Cu]C#N
Agent: [Fe+2]
Agent: [Pd]
Agent: CC[N+](CC)(CC)CC
Solvent: CN(C)C=O
Product: CCCc1n[nH]c(C(=O)OCC)c1C#N
Temperature: 120 °C
Reaction time: 5 h

Procedure:
1.5 g (4.9 mmol) of 4-Iodo-5-propyl-2H-pyrazole-3-carboxylic acid ethyl ester, 0.87 g (9.7 mmol) of copper cyanide and 404 mg (2.4 mmol) of tetraethylammonium cyanide were dissolved in 10 ml of DMF and 20 ml of tetrahydrofuran and the solution was degassed with argon. 223 mg (0.2 mmol) of Tris(dibenzylideneacetone)dipalladium (0) and 404 mg (0.7 mmol) of 1,1′-bis-(diphenylphosphino) ferrocene were added at RT. The reaction was stirred at 120° C. for 5 h. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and this solution was washed with saturated aqueous sodium bicarbonate. The organic phase was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography eluting with n-heptane:ethyl acetate/ 1:1.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)=[NH:5])#[N:2].Cl.[CH2:16]1[O:26][C:25]2[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][C:18]=2[O:17]1>>[ClH:13].[Cl:14][C:9]1[CH:8]=[C:7]([NH:6][C:4]([NH:3][C:1]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:25]3[O:26][CH2:16][O:17][C:18]=3[CH:19]=2)=[NH:2])=[NH:5])[CH:12]=[CH:11][C:10]=1[Cl:13]
Reactant: NCc1ccc2c(c1)OCO2
Reactant: N#CNC(=N)Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: N=C(NCc1ccc2c(c1)OCO2)NC(=N)Nc1ccc(Cl)c(Cl)c1
Yield: 139.6 %

Procedure:
Using 21.5 g of N1 -cyano-N3 -(3,4-dichlorophenyl)-guanidine and 18.8 g of 3,4-methylenedioxybenzylamine hydrochloride, 27.3 g of the captioned compound was obtained by operating the same manner as in Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[CH3:13][O:14][C:15]1[C:25]([O:26][CH3:27])=[C:24]([O:28][CH3:29])[CH:23]=[CH:22][C:16]=1[CH:17]=[CH:18][C:19](O)=O>>[CH3:13][O:14][C:15]1[C:25]([O:26][CH3:27])=[C:24]([O:28][CH3:29])[CH:23]=[CH:22][C:16]=1/[CH:17]=[CH:18]/[C:19]1[NH:1][C:2]2[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1OC
Product: COc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)c(OC)c1OC
Yield: 34.5 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 5.00 g (29.4 mmol) of 5,6-diamino-1,3-dimethyluracil and 7.71 g (32.4 mmol) of 2,3,4-trimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from isopropanol/water to give 3.78 g (yield 35%) of Compound 82 as an ocher powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:15]([CH2:18][C:19]([N:21]([CH:31]1[CH2:33][CH2:32]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[Cl:30])=[O:20])[CH2:16][OH:17])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[I-].[Na+].[CH3:45][O:46][CH2:47]Cl>COCCOC>[C:1]([O:5][C:6]([N:8]([C@@H:15]([CH2:18][C:19]([N:21]([CH:31]1[CH2:32][CH2:33]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[Cl:30])=[O:20])[CH2:16][O:17][CH2:45][O:46][CH3:47])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCl
Reactant: COC(=O)CCN(C(=O)OC(C)(C)C)[C@H](CO)CC(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: COCOC[C@H](CC(=O)N(Cc1cccc(Cl)c1Cl)C1CC1)N(CCC(=O)OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 53.1 %

Procedure:
Into a 250 mL round bottom flask was added 4D (12.42 g, 24.7 mmol) and DME (137 mL). Di-isopropylethylamine (DIEA) or Hunig's base (23.6 mL, 135.7 mmol, 5.5 eq) and sodium iodide (14.79 g, 98.7 mmol, 4.0 eq) was added to the solution and cooled with an ice bath. Methoxymethyl chloride (MOMCl) (10.7 mL, 127.1 mmol, 5.15 eq) was added slowly at 0° C. The reaction was allowed to warm to room temperature overnight. Solvent was removed under vacuum and the residue was portioned between water (150 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layers were combined and washed once with brine (100 mL). The organic phase was dried over sodium sulfate and filtered. Solvent was removed under vacuum and the residue was purified by column chromatography (30% ethyl acetate/hexanes) to give 4E (7.18 g, 53%) as a viscous oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.87 (m, 4H) 1.46 (br. s., 9H) 2.63 (br. s., 4H) 3.36 (s, 3H) 3.66 (s, 8H) 4.06-4.30 (m, 1H) 4.62 (m, 3H) 4.79 (m, 1H) 6.94 (d, J=7.83 Hz, 1H) 7.11-7.17 (m, 1H) 7.36 (dd, J=8.08, 1.26 Hz, 1H). ESI-MS:m/z 547.4 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][CH:15]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:16][C:17]([OH:19])=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Cl.[CH3:29][NH:30][CH3:31].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][CH:15]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)[CH2:16][C:17]([N:30]([CH3:31])[CH3:29])=[O:19])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CNC
Reactant: Cc1ccc2c(c1)c1c(n2CC(CC(=O)O)c2ccncc2)CCN(C)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)c1c(n2CC(CC(=O)N(C)C)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.1 %

Procedure:
4-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyric acid (130 mg, 0.358 mmol) was dissolved in DCM (5 mL), dimethyl amine hydrochloride (57 mg, 0.716 mmol), PYBOP (223 mg, 0.429 mmol) and triethylamine (0.51 mL, 3.58 mmol) were added and the reaction mixture was stirred at RT for 4 h. The reaction progress was monitored by LC-MS. After completion of the reaction, the reaction mixture was concentrated and the crude product was purified by reverse phase chromatography to obtain 77 mg of 4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-N,N-dimethyl-3-pyridin-4-yl-butyramide as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.56 (d, 2H), 7.28 (d, 2H), 7.19 (s, 1H), 7.17 (d, 1H), 6.94 (d, 1H), 4.63 (dd, 1H), 4.54 (dd, 1H), 4.39 (d, 1H), 4.37 (t, 1H), 4.0 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.45 (m, 1H), 3.3 (m, 1H), 3.1 (s, 6H), 3.0 (d, 3H), 2.9 (m, 2H), 2.8 (d, 3H). Separation by chiral HPLC provides enantiomers II-230a-b.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].Br[CH2:7][CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1.O1CCCC1.C([N-]C(C)C)(C)C.[Li+]>CCOCC.C1CCCCC1>[CH3:3][C:2]([CH3:4])([CH2:7][CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1)[C:1]#[N:5]
Reactant: CC(C)C#N
Reactant: BrCCC1OCCO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C#N)CCC1OCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To a stirring solution of 25.1 g of isobutyronitrile and 61.0 g of 2-(2-bromoethyl)-1,3-dioxolane in 300 ml of anhydrous ether was slowly added 310 ml of a 1.5M solution of lithiumdiisopropylamide mono(tetrahydrofuran) in cyclohexane at 0°-5° C. After removal of the cooling bath, the reaction mixture was stirred for 4 hours at room temperature, treated with a saturated solution of ammonium chloride and worked up with ether. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated to give 61 g of a crude oil. Purification of this material on a silica gel column (eluting system:ether-hexane 4:1) afforded 47.9 g (77.9%) of α, α-dimethyl-1,3-dioxolane -2-butanenitrile. A solution of 47.9 g of α,α-dimethyl-1,3dioxolane-2-butanenitrile in 500 ml of anhydrous ethyl ether was treated with 200 ml of 1.4M methyllithium solution in ether at 0°-5° C. The reaction mixture was stirred for 2 hours at room temperature, treated with a saturated ammonium chloride solution and worked up with ether. The ethereal solution was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 39.2 g of a crude yellow oil. This material was treated with 70 ml of 4N-sulfuric acid and refluxed for 13 hours. After being cooled, the mixture was extracted with ether. The organic phase was washed with water, a saturated solution of sodium bicarbonate, water, dried over anhydrous magnesium sulfate and concentrated to give 23.1 g (65.8%) of 6,6-dimethyl-2-cyclohexen-1-one as an orange oil. This material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=2)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.CCOC(C)=O>[CH2:22]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=2)[CH:13]=[C:5]1[C:3]([O:2][CH3:1])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(OC)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of methyl6-methoxy-1H-indole-2-carboxylate (Compound 1, 1.0 g, 4.9 mmol) in DMF (10 ml) was added K2CO3 (2.0 g, 14.6 mmol) and benzyl bromide (0.87 ml, 7.3 mmol). The mixture was stirred at room temperature for 40 h and was diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by crystallization from Et2O to yield the title compound as an off-white solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)=[CH:8][CH:9]=2)[N:4]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[C:10]3[C:5](=[CH:6][C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=4)=[CH:8][CH:9]=3)[N:4]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH:3]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1cccc(-c2ccc3c(Br)cn(-c4ccncc4)c3c2)c1
Product: COc1ccc(-c2cn(-c3ccncc3)c3cc(-c4cccc([N+](=O)[O-])c4)ccc23)cc1

Procedure:
The target compound was prepared as in Example 13 using 3-bromo-6-(3-nitrophenyl)-1-(pyridin-4-yl)-1H-indole (97 mg, 0.222 mmol) and 4-methoxyphenylboronic acid (37 mg, 0.244 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20]([NH:22][O:23]C3CCCCO3)=[O:21])[CH:16]=2)[CH2:11]1)=[O:9].[ClH:30]>O.CO>[ClH:30].[OH:23][NH:22][C:20]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([C:8](=[O:9])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH2:19][CH2:18]2)=[O:21]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)Cc1ccccn1)C2
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C(NO)c1ccc2c(c1)CCN(C(=O)Cc1ccccn1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 75 mg 2-(pyridin-2-ylacetyl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide and 6 ml of a 0.1M solution of HCl in water in 4 ml methanol is stirred overnight at ambient temperature and evaporated. The mixture is dissolved in a mixture of 2 ml water and 2 ml acetonitrile and lyophilized. 75 mg of the title compound are obtained as colorless solid. MH+=312.1
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48](=[O:50])[CH3:49])=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:9][O:8][C:3]1[C:2]([NH:1][C:43](=[O:44])[C:42]2[CH:46]=[C:38]([CH2:37][C:31]3[C:32](=[O:36])[C:33]([O:34][CH3:35])=[C:28]([O:27][CH3:26])[C:29](=[O:52])[C:30]=3[CH3:51])[CH:39]=[CH:40][C:41]=2[O:47][C:48](=[O:50])[CH3:49])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: COc1ncccc1N
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccnc3OC)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.8 %

Procedure:
3-Amino-2-methoxypyridine (0.149 g, 1.203 mmol), triethylamine (0.122 g, 1.203 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.203 g, 1.203 mmol) were added to a methylene chloride solution (150 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.300 g, 0.802 mmol) and the resulting solution was stirred at room temperature for 4 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=50:1) to obtain the titled compound (0.250 g, 0.520 mmol, 65%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].I[CH2:21][CH2:22][CH2:23][CH3:24]>CS(C)=O>[CH2:21]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCI
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCn1ccc2cc(C(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of methyl 1H-indole-5-carboxylate (6.0 g) in methylsulfoxide (30 mL) was added potassium t-butoxide (3.88 g). The mixture was stirred at room temperature for 10 minutes at which time 1-iodobutane (1.8 mL) was added. The mixture was stirred at room temperature for 5 h then partitioned between water and methylene chloride. The layers were separated and the organic layer washed three times with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 10% ethyl acetate in hexanes as eluent to give 6.18 g of the title compound: 1H NMR (CDCl3) δ 0.923, 1.38, 1.83, 3.9, 4.14, 6.58, 7.15, 7.34, 7.9, 8.39.
Reaction SMILES: [C:1]([O:6]CC)(=O)[C:2]([CH3:4])=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:18]([NH2:27])=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[C:17]3[C:18](=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=3)[N:27]=[C:2]([CH3:4])[C:1]2=[O:6])=[CH:14][CH:15]=1
Reactant: Nc1cc(C(F)(F)F)ccc1Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)=O
Product: Cc1nc2cc(C(F)(F)F)ccc2n(-c2ccc(Cl)cc2)c1=O

Procedure:
Preparation as in Example 1 but using ethyl pyruvate and N-(4-chlorophenyl)-4-trifluoromethylbenzene-1,2-diamine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].S(=O)(=O)(O)O.[CH:10](O)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][O:4][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: OCCCl
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: ClCCOC(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 100.1 %

Procedure:
To a solution of 3.27 g of 2-chloroethanol in dry benzene (3.5 ml) was added 0.8 g of conc. sulfuric acid and the mixture was heated, under argon atmosphere, at 50° C. To the mixture was added slowly a solution of 5.0 g of benzhydrol in dry benzene (6.5 ml) and, after 30 minutes from the addition, the whole mixture was refluxed for 1.5 hours. After the mixture was allowed to cool, the benzene layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, to give 6.7 g of benzhydryl 2-chloroethyl ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.S(=O)(=O)=O.N1C=CC=CC=1>C(Cl)Cl.CS(C)=O.CCOC(C)=O>[CH2:12]([C@:8]([NH:7][C:6](=[O:19])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:11])[CH:9]=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CO)Cc1ccccc1
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@@](C)(C=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of tert-butyl((1R)-1-benzyl-2-hydroxy-1-methylethyl)carbamate (6.7 g, 25.2 mmol) in DCM (100 mL) and DMSO (25 mL) was added triethylamine (10.5 mL, 75.7 mmol) and sulfurtrioxide-pyridine (10 g, 63.1 mmol). The reaction mixture was stirred at rt for 3.5 h, diluted with EtOAc, washed with 10% KHSO4, saturated NaHCO3, water, brine and aq LiCl, dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (silica, 0-20% EtOAc/hexanes) to provide tert-butyl ((1R)-1-benzyl-1-methyl-2-oxoethyl)carbamate as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 7.35-7.22 (m, 3H), 7.12-7.00 (m, 2H), 4.84 (br s, 1H), 3.17 (A of AB, d, J=13.6 Hz, 1H), 3.08 (B of AB, d, J=13.6 Hz, 1H), 1.51 (s, 9H), 1.27 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)=[N:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.Br[CH2:33][C:34]([NH2:36])=[O:35].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)=[N:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:33][C:34]([NH2:36])=[O:35])[CH2:21][CH2:20]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: NC(=O)CBr
Reactant: Cc1cc(Nc2nc(Nc3ccc(C4CCNCC4)c4ccccc34)ncc2Cl)n[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3ccc(C4CCN(CC(N)=O)CC4)c4ccccc34)ncc2Cl)n[nH]1
Temperature: 130 °C

Procedure:
A mixture of 5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)-N2-(4-(piperidin-4-yl)naphthalene-1-yl)pyrimidine-2,4-diamine (30.8 mg, 0.07 mmol), 2-bromoacetamide (19.6 mg, 0.14 mmol) and triethylamine (30.0 μL, 0.21 mmol) in 2 mL of DMF was heated at 130° C. in a microwave reactor for 20 min. The crude product was purified by RP-HPLC to afford 2-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)naphthalene-1-yl)piperidin-1-yl)acetamide; ESMS m/z 491.2 (M+H+).