Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:11][CH2:10][N:9](C(OCC)=O)[CH2:8][CH2:7][C:6]=2[N:17]=1.[OH-].[K+]>C(O)C>[NH2:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[N:17]=1
Reactant: CCOC(=O)N1CCc2ncc(N)nc2CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cnc2c(n1)CCNCC2
Temperature: 100 °C

Procedure:
11.15 gm (47.2 mmols) of ethyl 2-amino-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine-7-carboxylate were dissolved in 300 ml of ethanol, and the solution was admixed with 30 gm of potassium hydroxide. The mixture was evaporated to dryness, and the residue was heated for 3 hours at 100° C. and then taken up in water. The aqueous solution was extracted with chloroform with the aid of a heavy phase perforator, and the chloroform extract solution was purified on a silicagel column with chloroform/methanol/concentrated ammonia (24:12:1) as the mobile phase.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:16]=[C:15]([CH:17]=O)[CH:14]=[CH:13][CH:12]=3)[S:10][C:3]=12.[CH3:19][NH:20][CH3:21].[BH3-]C#N.[Na+].CC([O-])=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:16]=[C:15]([CH2:17][N:20]([CH3:21])[CH3:19])[CH:14]=[CH:13][CH:12]=3)[S:10][C:3]=12
Reactant: CNC
Reactant: O=Cc1cccc(-c2cc3nccc(Cl)c3s2)n1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)Cc1cccc(-c2cc3nccc(Cl)c3s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of 6-(7-chlorothieno[3,2-b]pyridin-2-yl)pyridine-2-carbaldehyde 52a (0.127 g, 0.46 mmole) in THF (20 ml) was added 2.0 M dimethylamine in THF (1.5 ml, 2.3 mmole), NaCNBH3 (0.063 g, 0.92 mmole) and NaOAc (0.076 g, 0.92 mmole). The reaction mixture was stirred at room temperature overnight and concentrated. The residue was purified by flash column chromatography eluting with 2-10% CH3OH in CHCl3 to give a yellow solid (0.086 g, 61%). 1H NMR (300 MHz, CD3OD) δ8.50 (1H, d, J=5.3 Hz), 8.11 (1H, s), 8.03 (1H, d, J=7.9 Hz), 7.90 (1H, t, J=7.9 Hz), 7.41 (2H, m), 4.16 (2H, s), 2.71 (6H, s).
Reaction SMILES: Cl[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[CH:7]=O.[SH:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C>N1C=CC=CC=1>[S:9]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:3]2[CH2:4][CH2:5][CH2:6][C:2]1=2
Reactant: COC(=O)CS
Reactant: O=CC1=C(Cl)CCC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COC(=O)c1cc2c(s1)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a 100-mL round-bottom flask containing a solution of 2-chlorocyclopent-1-ene-1-carbaldehyde (1.2 g, 9.19 mmol, 1.00 equiv) and methyl 2-sulfanylacetate (1.17 g, 11.02 mmol, 1.20 equiv) in pyridine (10 mL) was added triethylamine (2 mL) dropwise at 0° C. The resulting solution was stirred for 1 h at room temperature. The reaction was then quenched by the addition of 2 mL of 48% aqueous KOH solution and diluted with 100 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 1.3 g (78%) of methyl 4H,5H,6H-cyclopenta[b]thiophene-2-carboxylate as a yellow solid. MS (ES): m/z 183 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=[O:31])OC3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:31])=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C1CCNCC1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)N1CCCCC1

Procedure:
Piperidine-1-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate M and piperidine. MS calcd. for C22H23ClN3O2 [(M+H)+] 396.1, obsd. 395.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCl.[CH:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1>C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([S:36]([CH:33]4[CH2:35][CH2:34]4)(=[O:38])=[O:37])[CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCNCC3)cn2)c2ccccc21
Reactant: O=S(=O)(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCN(S(=O)(=O)C4CC4)CC3)cn2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
10 g of 4-(5-(piperazin-1-yl)pyridin-2-yl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are placed in a 500 ml round-bottomed flask. 126 ml of dichloromethane are added, followed by 4.23 ml of triethylamine and, finally, 2.7 ml of cyclopropylsulphonyl chloride. The reaction mixture is stirred at ambient temperature for 16 h, then washed with water and once with a saturated sodium chloride solution, dried over magnesium sulphate and then evaporated under reduced pressure. The crude product obtained is chromatographed on silica gel, elution being carried out with a gradient of methanol in dichloromethane varying from 0% to 10%. 10.9 g of 4-[5-(4-(cyclopropylsulphonyl)piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are obtained.
Reaction SMILES: [Si]([O:18][C@H:19]1[CH2:26][CH2:25][CH2:24][O:23][CH2:22][O:21][CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([O-])(O)=O.[Na+]>C1COCC1>[C@H:19]1([OH:18])[CH2:26][CH2:25][CH2:24][O:23][CH2:22][O:21][CH2:20]1
Reactant: CC(C)(C)[Si](O[C@H]1CCCOCOC1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: O[C@H]1CCCOCOC1
Temperature: 23 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
Compound 7a (0.27 g, 0.74 mmol) was dissolved in dry THF (5 mL) and TBAF (1.0 M solution in THF, 0.81 mL, 0.81 mmol) was added. The resulting mixture was stirred at 23° C. overnight, afterward a saturated solution of NaHCO3 was added, the solvent was removed and the aqueous phase was extracted with EtOAc. The organic extracts were dried and evaporated and the residue was purified by flash-chromatography (EtOAc) to afford 76 mg (77%) of 8a as a colourless oil: [α]D20, −12.6 (c 1.6, CHCl3); 1H NMR (CDCl3) δ 4.65 (d, J=6.0 Hz, 1H), 4.57 (d, J=6.0 Hz, 1H), 4.92-3.81 (m, 2H), 3.75-3.60 (m, 2H), 3.55 (dd, J=3.4, 12.1 Hz, 1H), 2.96 (bs, 1H), 1.95-1.69 (m, 3H), 1.65-1.53 (m, 1H); 13C NMR (CDCl3) δ 94.9, 73.7, 69.3, 68.2, 30.2, 24.7.
Reaction SMILES: [OH-].[Na+].Cl.[CH2:4]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C:21]([NH2:23])=[NH:22])[CH:15]=[CH:14]2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:24]1([CH3:30])[CH:29]=[CH:28]C=C[CH:25]=1>CO>[CH2:4]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:21]3[N:23]=[CH:30][C:24]([CH2:29][CH3:28])=[CH:25][N:22]=3)[CH:17]=2)[CH:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCc1ccc2cc(C(=N)N)ccc2c1
Reactant: Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCc1ccc2cc(-c3ncc(CC)cn3)ccc2c1
Temperature: 60 °C
Yield: 60 %

Procedure:
NaOH (1.1 g, 26 mmols) was added to anhydrous methanol (40 ml) and dissolved therein by heating to 60° C. with stirring. To the solution was added 6-heptyl-2-naphthalenecarboxamidine hydrochloride (4.0 g, 13 mmols) to prepare a suspension with stirring. To this suspension was dropwise added over one minute a solution obtained by dissolving α-ethyl-β-dimethylaminoacrolein (1.7 g, 13 mmols) in anhydrous methanol (5 ml), followed by gently refluxing the mixture with stirring for 2 hours, distilling off methanol under the atmospheric pressure after completion of the reaction, adding toluene (50 ml) to the residue to extract the resulting product, washing the extraction solution with a 2N-NaOH aqueous solution and then with water, drying over anhydrous sodium sulfate, and distilling off toluene under reduced pressure to obtain solids, which were then recrystallized from ethanol to obtain the objective 2-heptyl-6-(5-ethyl-2-pyrimidinyl)naphthalene (2.5 g, 7.8 mmols) (yield: 60%). M.P.: 62.3°-63.1° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[S:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=3)[S:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1ccc(Cc2cc(OC3CCCC3)cs2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(Cc2cc(OC3CCCC3)cs2)cc1
Temperature: 75 °C
Yield: 40.9 %

Procedure:
To a solution of 4-(4-cyclopentyloxythien-2-ylmethyl)-nitrobenzene (1.28 g, 4.2 mmol) in absolute ethanol (34 mL) was added tin dichloride hydrate (4.76 g, 21.2 mmol) at 20-25° C. under nitrogen. The mixture was heated at 75° C. for 2.5 hours and cooled to 0-5° C. Saturated sodium bicarbonate was added to pH 8. Ethyl acetate was added and the mixture was filtered. The layers were separated, and the aqueous phase was extracted with additional ethyl acetate. The combined organic phases were washed with brine, dried (Na2SO4), and concentrated to dryness. Purification by flash chromatography (silica, hexane/ethylacetate) gave 4-(4-cyclopentyloxythien-2-ylmethyl)-phenylamine (0.47 g, 41%) as a pale yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.03 (d,J=8.5 Hz, 2H), 6.63 (d,J=8.5 Hz 2H), 6.41 (m, 1H), 5.96 (d,J=1.7 Hz, 1H, 4.58 (quintet, J=4.3 Hz, 1H), 3.91 (S,2H), 3.59 (bs,2H), 1.67-1.88 (m, 6H), 1.46-1.67 (m, 2N).
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[N:4]([CH3:6])C.N1CCCC1.CO[C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([N+:23]([O-])=O)=CN=1>CN(C)C=O.[Pd]>[CH3:1][O:2][C:3]1[CH:22]=[C:20]2[CH:21]=[CH:16][NH:23][C:19]2=[CH:6][N:4]=1
Reactant: COC(OC)N(C)C
Reactant: COc1cc(C)c([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: COc1cc2cc[nH]c2cn1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
10.76 g of N,N-dimethylformamide dimethyl acetal and 2.45 ml of pyrrolidine are added, in succession, to a solution of 5 g of the product obtained in Step 1 in 60 ml of dimethylformamide. The mixture obtained is first heated at 100° C. for 8 hours and then at 150° C. for 1 hour. Concentration is carried out under a vacuum of 10−1 mbar and the residue is taken up in 150 ml of tetrahydrofuran. The solution obtained is hydrogenated under a pressure of 10 bars for 4 hours in the presence of 10% Pd/C. After filtration and concentration, the residue is chromatographed over silica (eluant CH2Cl2/EtOH: 95/5) to yield the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]#[N:17].[CH3:18][S:19]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](O)=[O:26])(=[O:21])=[O:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][C:16]#[N:17])[C:25](=[O:26])[C:24]1[CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=[C:22]([S:19]([CH3:18])(=[O:21])=[O:20])[CH:23]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: N#CCNc1cnccc1-c1ccccc1Cl
Product: CS(=O)(=O)c1cc(C(=O)N(CC#N)c2cnccc2-c2ccccc2Cl)cc(C(F)(F)F)c1
Yield: 25 %

Procedure:
The title compound was prepared in analogy to example 90, from [4-(2-chloro-phenyl)-pyridin-3-ylamino]-acetonitrile and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 6 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Another purification step using preparative HPLC (Gemini NX column) with a gradient of MeOH:water (containing 0.05% formic acid) (80:20 to 98:2) yielded the title compound as colorless solid (25%). MS (ESI): m/z=494.055 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:16])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:27](Cl)(=[O:31])[O:28][CH2:29][Cl:30]>C1COCC1>[CH:1]1([N:4]([C:5](=[O:16])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)[C:27](=[O:31])[O:28][CH2:29][Cl:30])[CH2:3][CH2:2]1
Reactant: O=C(Cl)OCCl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1[N+](=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)N(C(=O)OCCl)C2CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of N-cyclopropyl-4-methyl-3-nitrobenzamide (2.10 g, 9.5 mmol) in THF (48 mL) under nitrogen at −78° C. was added lithium bis(trimethylsilyl)amide (1M, THF, 11.4 mL) over 10 min. After 0.5 h, chloromethyl carbonochloridate (1.1 mL, 12.4 mmol) was added. After 10 min., the cold bath was removed, and the reaction was stirred to room temperature for 1.5 h, quenched with water and concentrated in vacuo. It was then diluted with EtOAc and water. After the layers were separated, the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel chromatography using hexanes:EtOAc (5:1) as eluent afforded the title compound as a colorless oil (2.14 g, 72% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][CH:12]([CH3:15])[CH2:13][OH:14]>>[NH2:1][C:2]1[CH:9]=[C:8]([O:14][CH2:13][CH:12]([CH3:15])[CH3:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: CC(C)CO
Reactant: N#Cc1cnc(N)cc1F
Product: CC(C)COc1cc(N)ncc1C#N

Procedure:
From intermediate 21 and 2-methylpropan-1-ol, reacted in an analogous manner to the preparation of intermediate 89. 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.86 (s, br, 2H), 6.04 (s, 1H), 3.79 (d, 2H), 2.06-1.96 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][N:27]1[CH:31]=[CH:30][C:29]([NH2:32])=[N:28]1.CC(C)([O-])C.[Na+].CN(C=O)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:32][C:29]3[CH:30]=[CH:31][N:27]([CH3:26])[N:28]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Cn1ccc(N)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cn1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)n1
Temperature: 140 °C
Yield: 67.5 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (200 mg, 468 μmol), 1-methyl-1H-pyrazol-3-amine (68.2 mg, 702 μmol), BINAP (14.6 mg, 23.4 μmol), palladium (II) acetate (26.3 mg, 117 μmol) and sodium tert-butoxide (112 mg, 1.17 mmol) was added DMF (1.01 mL) and toluene (503 μL) was heated in a microwave at 140° C. for 20 min. The reaction mixture was cooled then diluted with water and extracted into ethyl acetate. The organic layers were combined and washed with brine and then dried over magnesium sulfate. Purification by chromatography (silica, 20-100% ethyl acetate in hexanes) gave N-tert-butyl-2-(1-methyl-1H-pyrazol-3-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (140 mg, 316 μmol, 67%) as a yellow solid. MS (EI/CI) m/z: 444.3.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@H:4]([CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[Na+]>>[NH2:22][C:16]1[CH:17]=[C:18]([Br:21])[CH:19]=[CH:20][C:15]=1[S:14][CH2:13][C@@H:4]([NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[C:3]([OH:23])=[O:2]
Reactant: COC(=O)[C@H](CSc1ccc(Br)cc1N)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N[C@H](CSc1ccc(Br)cc1N)C(=O)O

Procedure:
100 mg (0.242 mmol) of N-tert-butoxycarbonyl-3-(2-amino-4-bromophenylthio)-L-alanine methyl ester (98%) was added to a system consisting of 20% organic co-solvent (see following table) and 80% buffer solution (0.1M sodium chloride; 3 mM sodium phosphate pH 7.5) under vigorous stirring. 100 ul Alcalase 2.4 L [a subtilisin Carlsberg from Novo Nordisk] was added and the pH maintained at 7.5 under vigorous stirring by the controlled addition (pH-static) of 0.1N sodium hydroxide solution. At the end of the reaction, the conversion degree was determined by HPLC.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1.[NH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:9]1([NH:8][C:6]2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=[C:2]([NH:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]3)[N:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1NC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(N[C@H]2CC[C@H](O)CC2)nc1NC1CCCC1
Reaction time: 8 h

Procedure:
(2-Chloro-5-nitropyrimidin-4-yl)cyclopentylamine (6.18 mmol, 1.5 g.) and trans-4-aminocyclohexan-1-ol (7.42 mmol, 854 mg mL) were mixed in DMF (18 mL) and N,N-diisopropylethylamine (7.42 mmol, 1.29 mL) was added. The reaction mixture was stirred overnight. Solvent was removed in vacuo and the residue purified using column chromatography (SiO2, 1:1 n-hexanes/ethyl acetate→7:3 n-hexanes/ethyl acetate→ethyl acetate) to give the desired product (1.75 g, 88% yield). ES-MS: 322 (M+1). When the hydrochloride salt of an amine is used in place of the trans-4-aminocyclohexan-1-ol described above, 2 to 3 equivalents of N,N-diisopropylethylamine or sodium bicarbonate and tetrahydrofuran or acetonitrile were used as solvent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11](O)[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.S([Cl:34])(C)(=O)=O>C(Cl)Cl>[Cl:34][CH:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(O)C(=O)OCc2ccccc2)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(Cl)C(=O)OCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To 137D (450 mg, 1.5 mmol) in CH2Cl2 (5 mL) at 0° C. was added triethylamine (0.42 mL, 3.0 mmol) followed by mesyl chloride (0.14 mL, 1.8 mmol). After stirring at rt overnight, the reaction was concentrated and purified via silica gel chromatography (0-25% ethyl acetate/hexanes) to provide 137E (268 mg, 56%). 1H NMR (400 MHz, Methanol-d4) δ ppm 3.81 (s, 3H) 3.87 (s, 3H) 5.19 (m, 2H) 5.36 (s, 1H) 6.81 (d, J=8.35 Hz, 1H) 6.93-7.07 (m, 2H) 7.20-7.42 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([OH:11])[CH:5]=1.[C:13](Cl)(=O)[CH3:14].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]=[C:13]([CH3:14])[O:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: COC(=O)c1ccc2nc(C)oc2c1
Reaction time: 8.5 h
Yield: 80.3 %

Procedure:
To a solution of 4-amino-3-hydroxy-benzoic acid methyl ester (2085 mg, 12.47 mmmol) in xylene (200 mL) were added acetyl chloride (1.06 mL, 14.96 mmol), pyridinium p-toluenesulfonate (940 mg, 3.74 mmol) and triethylamine (2.09 mL, 14.96 mmol), and the solution was stirred for 8.5 hours under reflux. Ethyl acetate was added to the reaction mixture, which was then washed with water, dried over anhydrous magnesium sulfate, then, evaporated in vacuo, the resulting residue was purified by silica gel chromatography (hexane-ethyl acetate), and the title compound (1917 mg, 10.02 mmol, 80.4%) was obtained.
Reaction SMILES: B.[Cl:2][C:3]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:4]=1[O:5][CH:6]([CH3:10])[C:7](O)=[O:8].Cl>O1CCCC1.CO>[Cl:2][C:3]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:4]=1[O:5][CH:6]([CH3:10])[CH2:7][OH:8]
Reactant: CC(Oc1ccc(Cl)cc1Cl)C(=O)O
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(CO)Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 100.1 %

Procedure:
43 ml of a 1M solution of borane in tetrahydrofuran (THF) were stirred under nitrogen and cooled in ice while a solution of 6.8 g of 2-(2,4-dichlorophenoxy)propionic acid in 40 ml of THF was added dropwise thereto. The mixture was heated to boiling under reflux for 1 hour and then cooled to room temperature. 22 ml of a saturated solution of hydrogen chloride in methanol were added dropwise and the solution was heated to boiling under reflux for 1 hour. The mixture was evaporated and the residue was treated with 22 ml of a saturated solution of hydrogen chloride in methanol. After heating under reflux for 1 hour the mixture was evaporated and the residue was partitioned between 100 ml of saturated sodium bicarbonate solution and 100 ml of methylene chloride. The layers were separated and the aqueous layer was extracted with 100 ml of methylene chloride. The combined organic extracts were dried over sodium sulphate and evaporated to gave 6.4 g of 2-(2,4-dichlorophenoxy)propanol as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[CH3:32])[N:20]=[C:19]([CH3:33])[N:18]=2)=O)=[CH:6][C:5]=1[O:34][CH3:35])[CH3:2].[AlH3].N(CC)(C)C>C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:24]3[C:25]([CH3:32])=[CH:26][C:27]([CH3:31])=[CH:28][C:29]=3[CH3:30])[N:20]=[C:19]([CH3:33])[N:18]=2)=[CH:6][C:5]=1[O:34][CH3:35])[CH3:2]
Reactant: CCOc1ccc(CC(=O)NCCNc2cc(Nc3c(C)cc(C)cc3C)nc(C)n2)cc1OC
Agent: CCN(C)C
Agent: [AlH3]
Solvent: C1CCOC1
Product: CCOc1ccc(CCNCCNc2cc(Nc3c(C)cc(C)cc3C)nc(C)n2)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Heat a solution of 2-(4-ethoxy-3-methoxy-phenyl)-N-{2-[2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidin-4-ylamino]ethyl}-acetamide (0.324 g, 0.68 mmol) in THF (10 mL) with AlH3.NMe2Et (14 mL, 6.78 mmol) to reflux for 14 h. Cool the resulting mixture to ambient temperature, quench with Na2CO3.10H2O (1.0 g) and stir at ambient temperature for 15 min. Filter the solution through Celite and wash with several portions of CH2Cl2. Concentrate the filtrate in vacuo to dryness and purify by preparative TLC (10% MeOH in CH2Cl2) to obtain the title compound.