Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].Cl.[C:6]1([C@H:16]([NH:18][C@H:19]2[CH2:23][CH2:22][N:21]([C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[CH2:20]2)[CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[OH:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([N:21]2[CH2:22][CH2:23][C@H:19]([NH:18][C@@H:16]([C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=[CH:8][CH:7]=3)[CH3:17])[CH2:20]2)=[CH:25][CH:26]=1
Reactant: NCCO
Reactant: C[C@@H](N[C@H]1CCN(c2ccc(C(=O)O)cc2)C1)c1cccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](N[C@H]1CCN(c2ccc(C(=O)NCCO)cc2)C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
To a mixed solution of 7.7 mg of 2-aminoethanol and 50 mg of 4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoic acid hydrochloride (the compound obtained in Example 3.001) dissolved in 8 ml of dimethylformamide were added 22.2 mg of 1-hydroxybenzotriazole, 70 μl of triethylamine and 31.4 mg of EDC hydrochloride, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated, a saturated aqueous sodium bicarbonate solution and chloroform were added to the residue, and the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by NH thin layer silica gel chromatography (chloroform:methanol=39:1) and thin layer silica gel chromatography (chloroform:methanol=9:1) to give 22.6 mg of N-(2-hydroxyethyl)-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide. (2) To a solution of 22.6 mg of N-(2-hydroxyethyl)-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide dissolved in 1 ml of methylene chloride was added dropwise 3 ml of a solution of 4M hydrochloric acid in dioxane, and the mixture was stirred for a while. The reaction mixture was evaporated, and, to the residue was added tert-butanol to dissolve the same, and freeze-dried to obtain 25.6 mg of N-(2-hydroxyethyl)-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide hydrochloride (the following Table A3, Example 3.017).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC=NN)c1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NN=CNc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To the product of Example 3 (0.37 g, 0.0007 mole) in H2O (10 ml) was added LiOH (80 mg, 0.002 mole). The reaction mixture was stirred at room temperature for 1 hour. The pH was lowered to ≃3 with TFA and the product was isolated by RPHPLC to yield β-[[2-[[[3-[(aminoiminomethyl)amino]phenyl]carbonyl]-amino]acetyl]amino]benzenepropanoic acid, trifluoroacetate salt (280 mg) as a white solid. MS and NMR were consistent with the desired structure.
Reaction SMILES: [C:1]([NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=O)[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].P([C:36]#[N:37])(OCC)(OCC)=O>>[C:1]([NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17]([CH:18]=[C:19]([C:36]#[N:37])[CH2:20][CH2:21]1)=[CH:16][CH2:15]3)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCOP(=O)(C#N)OCC
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Following a procedure similar to that described in example 2(c), but using 100 mg of N-t-butyl-3-oxo-4-androstene-17β-carboxamide (prepared as described in Preparation 1), 0.2 ml of diethyl cyanophosphate and 200 mg of a boron trifluoride-diethyl ether complex, 86 mg of the title compound were obtained as a crystalline substance, melting at 198° to 200° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([B:30]2[O:38]C3C(C)(C4CC(C3)C4(C)C)O2)[CH2:14][C:15]2[C:16]([O:28]C)=[C:17]([CH:25]=[CH:26][CH:27]=2)[C:18]([O:20]C(C)(C)C)=[O:19])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl>>[OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]2[CH2:14][C:15]3[CH:27]=[CH:26][CH:25]=[C:17]([C:18]([OH:20])=[O:19])[C:16]=3[O:28][B:30]2[OH:38])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1c(C[C@H](NC(=O)Cc2ccc(O)c(O)c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: Cl
Product: O=C(Cc1ccc(O)c(O)c1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O

Procedure:
tert-Butyl 3-((2R)-2-(2-(3,4-dihydroxyphenyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate (200 mg) was mixed with 3 ml of 3N HCl and the reaction mixture was heated at reflux for 1 hr. The reaction solution was cooled and washed with dichloromethane three times. The crude product in the aqueous phase was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 358 (MH)+.
Reaction SMILES: [C:1]12(O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C.[C:27]1([CH:34]=[CH:33][CH:32]=[C:30]([OH:31])[CH:29]=1)[OH:28]>O>[OH:28][C:27]1[CH:29]=[C:30]([OH:31])[CH:32]=[CH:33][C:34]=1[C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: Oc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: Oc1ccc(C23CC4CC(CC(C4)C2)C3)c(O)c1
Reaction time: 3 h
Yield: 86 %

Procedure:
Into a four-neck flask having an inner volume of 500 ml and equipped with a reflux condenser, a stirrer, a thermometer, and a nitrogen inlet were charged 28.1 g (0.18 mol) of 1-adamantanol, 8.8 g (0.05 mol) of p-toluenesulfonic acid monohydrate, and 35 ml of ethanol. After the atmosphere was displaced by nitrogen, 39.6 g (0.36 mol) of resorcinol was added. The mixture in the flask was placed in an oil bath at 90° C. and heated and agitated for 3 hours. The reaction solution was cooled, added with 200 ml of pure water, agitated for 30 minutes, and then filtered to obtain a solid material. The material was dried under reduced pressure, then recrystallized from a methanol/toluene mixture solvent. The crystals obtained were collected with washing by toluene, and then dried under reduced pressure until constant weight to obtain the target compound (yield 86%).
Reaction SMILES: [C:1]([C:6]1[S:10][C:9]([C:11]([OH:13])=O)=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].C(Cl)(C([Cl:18])=O)=O>ClCCl.CN(C=O)C>[C:1]([C:6]1[S:10][C:9]([C:11]([Cl:18])=[O:13])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1ccc(C(=O)O)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C(=O)Cl)s1
Reaction time: 8 h

Procedure:
To a suspension of acid 35 (0.64 g, 3.2 mmol) in dichloromethane (20 mL) under argon at room temperature was added a 2.0M solution of (COCl)2 in dichloromethane (2.4 mL, 4.8 mmol) and two drops of DMF, and stirred overnight. Excess (COCl)2 and dichloromethane were removed at reduced pressure, and the viscous, light, yellow product was dried overnight to afford the desired benzoyl chloride 36 as a yellow solid. The structure of the product was also confirmed using IR and 1H NMR spectroscopy.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:31])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:18]([NH2:30])[CH:17]=2)=[CH:10][CH:9]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.[C:38]1([CH2:51][O:52][C:53](Cl)=[O:54])[C:50]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]=2[CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[CH2:1]([O:4][C:5](=[O:31])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:18]([NH:30][C:53]([O:52][CH2:51][C:38]3[C:50]4[CH2:49][C:48]5[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:42]=4[CH:41]=[CH:40][CH:39]=3)=[O:54])[CH:17]=2)=[CH:12][CH:13]=1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)OCc1cccc2c1Cc1ccccc1-2
Reactant: C=CCOC(=O)COc1ccc(COc2ccc(C(=O)c3ccccc3)c(N)c2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOC(=O)COc1ccc(COc2ccc(C(=O)c3ccccc3)c(NC(=O)OCc3cccc4c3Cc3ccccc3-4)c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
4-(3-Amino-4-benzoylphenoxymethyl)phenoxyacetic acid allyl ester (4.74 g, 11.4 mmol) and pyridine (1.09 g, 13.7 mmol, 1.2 equiv) were dissolved in 60 mL of CH2Cl2. The resulting yellow solution was cooled to 0° C., and fluorenylmethoxycarbonyl chloride (2.65 g, 1.14 mmol, 1.05 equiv) was added. The resulting solution was stirred at 0° C. for 15 min and then at ambient temperature for 1 h. The solution was diluted with CH2Cl2 (150 mL), extracted twice with 1N aqueous sodium bisulfate (100 mL), once with dilute aqueous sodium chloride (100 mL), and then concentrated to give a yellow foam. The unpurified product was crystallized from CH2Cl2 and hexanes to give 4.87 g (79% yield) purified material as a white solid: mp 96.5°-97.5° C. Rf 0.45 (CH2Cl2); IR (film from CH2Cl2, partial) 3230(b), 1740, 1610, 1575 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 4.32 (t, 1, J=7.4), 4.44 (s, 1, J=0.5), 4.71 (dd, 2, J=1.2, 5.9), 5.11 (s, 2), 5.26 (dd, 1, J=1.2, 10.4), 5.30 (dd, 1, J=1.4, 17.2), 5.85-598 (m, 2), 6.58 (dd, 2, J=2,5m 8.9) 6.92 (d, 2, J=8.8, 6.92 (q, 2, J=4.8, 9.6), 7.30-7.59 (m, 8), 7.63-7.70 (m,5), 7.76 (d, 2, J=8.9), 7.77 (d, 2, J=7.5), 8.29 (d, 1, J=2.3). 13C NMR (75.5 MHz, CDCl3) δ 47.3, 65.6, 66.2, 67.9, 70.0, 104.4, 109.6, 115.2, 115.8, 119.5, 120.4, 125.6, 127.5, 128.1, 128.8, 129.6, 129.8, 131.7, 131.9, 137.6, 140.0, 141.6, 144.1, 144.6, 154.1, 158.5, 164.1, 167.8, 199.1. Anal. Calcd for C40H33NO7 : C, 75.10; H, 5.20; N, 2.19. Found: C, 75.21; H, 5.33; N, 2.28.
Reaction SMILES: [NH2:1]/[C:2](/[C:7]#[N:8])=[C:3](\[NH2:6])/[C:4]#[N:5].[C:9](OC)(OC)(OC)[CH2:10][CH2:11][CH3:12]>>[CH2:10]([C:9]1[NH:1][C:2]([C:7]#[N:8])=[C:3]([C:4]#[N:5])[N:6]=1)[CH2:11][CH3:12]
Reactant: N#C/C(N)=C(/N)C#N
Reactant: CCCC(OC)(OC)OC
Product: CCCc1nc(C#N)c(C#N)[nH]1
Yield: 78.9 %

Procedure:
Following a procedure similar to that described in Preparation 1, but using 16.0 g of diaminomaleonitrile and 24 g of trimethyl orthobutyrate, 18.7 g of the title compound were obtained as crystals, melting at 141°-144° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([O:13]C)=[O:12])[CH2:7][N:6]1[S:15]([CH3:18])(=[O:17])=[O:16])=[O:4].[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7][N:6]1[S:15]([CH3:18])(=[O:17])=[O:16])=[O:4]
Reactant: COC(=O)C1CCC(C(=O)OC)N(S(C)(=O)=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C1CCC(C(=O)O)CN1S(C)(=O)=O
Reaction time: 0.75 h
Yield: 38 %

Procedure:
To a solution of (2RS,5RS)-1-methanesulfonyl-piperidine-2,5-dicarboxylic acid dimethyl ester (46.5 g) in methanol (850 ml) and water (85 ml) was added 1 molar sodium hydroxide (166 ml) within 20 minutes at reflux temperature. The reaction mixture was stirred for 45 minutes at reflux, cooled and concentrated. The residue was taken up in water (300 ml) and washed with Et2O. The aqueous phase was acidified with 1 molar HCl (166 ml) and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulphate and concentrated. The residue was crystallized from acetone/Et2O to obtain (2RS,5RS)-1-methanesulfonyl-piperidine-2,5-dicarboxylic acid 2-methyl ester (16.8 g) as a colourless solid, mp 130-133° C., MS: 206 (M+-59).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=2)=[CH:8][C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:11]=2)=[CH:8][C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1cc(-c2ccnc(S(C)(=O)=O)n2)n(C(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccnc(Oc3ccccc3)n2)n(C(C)(C)C)n1
Yield: 77 %

Procedure:
50 mg (0.142 mmol) of ethyl 1-tert-butyl-5-[2-(methylsulfonyl)pyrimidin-4-yl]-1H-pyrazole-3-carboxylate were dissolved in 1.5 mL of dry DMF, 14.7 mg (0.156 mmol) of phenol and 59 mg (0.426 mmol) of potassium carbonate were added. The final suspension was stirred at 70° C. for 3 h then partitioned between H2O and AcOEt. The organic layer was washed with brine dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:14])[C:9](=O)[CH2:10][C:11]#[N:12])[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[NH2:22][OH:23]>C(O)C.N1C=CC=CC=1>[NH2:12][C:11]1[O:23][N:22]=[C:9]([CH:8]([C:6]2[CH:5]=[CH:4][C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:2]([F:1])[CH:7]=2)[CH3:14])[CH:10]=1
Reactant: NO
Reactant: CC(C(=O)CC#N)c1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1cc(N)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To 4-(2-Fluoro-4-biphenylyl)-3-oxo-pentanenitrile (2.75 g, 10.3 mmol) in ethanol (70 ml) was added hydroxylamine hydrochloride (1.1 g, 15.8 mmol) in pyridine (10 ml). After addition, the mixture was stirred at room temperature overnight, then evaporated under reduced pressure to a residue, which was chromatographed and then recrystalyzed to afford 5-amino-3-(1-(2-fluoro-4-biphenylyl)ethyl)isoxazole (2.20 g, 76% yield) as crystalline material: mp 122°-123° C.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg+2].[Cl-].[Cl-].[CH2:19]=[O:20].Cl>C(#N)C>[OH:15][C:11]1[CH:10]=[C:9]([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH2:8])[CH:14]=[CH:13][C:12]=1[CH:19]=[O:20]
Reactant: C=O
Reactant: C=C(c1ccccc1)c1cccc(O)c1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: C=C(c1ccccc1)c1ccc(C=O)c(O)c1
Reaction time: 2 h
Yield: 90.5 %

Procedure:
A mixture of the phenol from step 2 (4.15 g, 21.1 mmole), MgCl2 (3.02 g, 31.7 mmole), TEA (11.1 mL, 79.3 mmole) and paraformaldehyde (4.29 g, 143 mmole) in anhydrous acetonitrile (100 mL) was refluxed for 17 h. Additional MgCl2 (1.5 g, 15.8 mmole), TEA (5.6 mL, 40 mmole) and paraformaldehyde (2.23 g, 74 mmole) were then added and reflux was continued for 2 h. The mixture was then cooled, acidified with 1N HCl and extracted with EtOAc (2×200 mL). The combined extracts were washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by filtration through a silica-gel plug (9:1 hexanes:EtOAc) to give 4.28 g (91% yield) of the product as a yellow oil: EIHRMS m/z 224.0837 (M+, C15H12O2, Calc'd 224.0837).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][CH:24]([C@@H:26]5[CH2:29][C@H:28](OS(C)(=O)=O)[CH2:27]5)[CH3:25])=[O:22])=[CH:19][N:18]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[C-:43]#[N:44].[K+].C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[C:43]([C@H:28]1[CH2:29][C@H:26]([CH:24]([NH:23][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:40])[CH3:41])[CH:19]=2)=[O:22])[CH3:25])[CH2:27]1)#[N:44]
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](OS(C)(=O)=O)C1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@H](C#N)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
To a solution of methanesulfonic acid cis-3-(1-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-cyclobutyl ester (crude from step 1, 114 mg, 0.19 mmol) in DMSO (1.5 mL) at room temperature was added potassium cyanide (48 mg, 0.74 mmol). The reaction mixture was heated at 60° C. for 2.5 h. 18-Crown-6 (10 mg, 0.04 mmol) was added and heated was continued at 80° C. for 2 h then at 100° C. overnight. The reaction was cooled to room temperature, quenched with water, and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was purified via chromatography with 30% to 50% EtOAc/hexanes to isolate 46 mg (45%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(trans-3-cyano-cyclobutyl)-ethyl]-amide as a yellow foam.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:16](Cl)=[O:17])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:8]=1)[CH3:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][C:35]=1[F:41]>N1C=CC=CC=1.CCOC(C)=O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH:38][C:16]([C:5]2[C:4]([O:3][CH2:1][CH3:2])=[CH:8][N:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[N:6]=2)=[O:17])=[CH:36][C:35]=1[F:41]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: CCOc1cn(-c2ccc(F)cc2)nc1C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOc1cn(-c2ccc(F)cc2)nc1C(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(F)c1
Reaction time: 8 h
Yield: 51.6 %

Procedure:
Acid chloride D4 (0.17 mmol, 1.0 eq.) was dissolved in dry pyridine (1.5 mL) at 0° C. and A2 (34 mg, 0.11 mmol, 0.65 eq.) was added. The reaction was allowed to reach RT overnight. The mixture was diluted with EtOAc and washed twice with aq. KOH-solution (0.5N), twice with aq. sat. NH4Cl-solution, and finally once with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (DCM/MeOH=100:0 to 10:1) to yield the desired product D5 (31 mg, 52% over 2 steps) as a white solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.38 (t, J=7.0 Hz, 3H), 3.94 (s, 6H), 4.09 (q, J=7.0 Hz, 2H), 6.48 (d, J=5.3 Hz, 1H), 7.43 (m, 4H), 7.53 (s, 1H), 7.70 (d, J=9.4 Hz, 1H), 8.01 (m, 3H), 8.47 (m, 2H), 10.17 (s, 1H). MS (ES) C29H24F2N4O5 requires: 546. Found: 547 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:9][C:10]2([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[C:16]([O:15][C:13]([C:10]1([O:9][C:3]2[C:2]([NH:1][CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=2)[CH2:12][CH2:11]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)C1(Oc2ncc(Cl)cc2N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)cnc2OC2(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 75 °C
Reaction time: 20 h
Yield: 54.7 %

Procedure:
At room temperature, to a 1,2-dichloroethane solution (280 ml) of tert-butyl 1-[(3-amino-5-chloropyridin-2-yl)oxy]cyclopropanecarboxylate (7.88 g) were added tert-butyl 4-oxopiperidine-1-carboxylate (22.1 g) and sodium triacetoxyborohydride (23.5 g), and then temperature was raised to 75° C., followed by stirring for 20 hours. After the temperature was brought back to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, and extracted with dichloromethane. The collected organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-[(2-{[1-(tert-butoxycarbonyl)cyclopropyl]oxy}-5-chloropyridin-3-yl)amino]piperidine-1-carboxylate (7.09 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[CH:12]=[C:13]([Br:16])[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)(=O)=O.[CH3:19][O:20][CH2:21][C:22]#[CH:23]>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]2[O:9][CH:8]=[C:7]([C:23]#[C:22][CH2:21][O:20][CH3:19])[C:11]=2[CH:12]=1
Reactant: O=S(=O)(Oc1coc2ccc(Br)cc12)C(F)(F)F
Reactant: C#CCOC
Product: COCC#Cc1coc2ccc(Br)cc12

Procedure:
Analogously to residue 9a, 9.31 g of 5-bromobenzofuran-3-yl trifluoromethanesulphonate [440083-74-9] and 3.52 ml of 3-methoxypropyne are reacted. The title compound is obtained as a yellowish oil. Rf=0.43 (1:10 EtOAc-heptane). Rt=5.14 (gradient I).
Reaction SMILES: C(O)C.Br[C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=1[CH:11]=[O:12].[N+:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:13]([C:16]1[CH:21]=[C:20]([C:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:11]=[O:12])[CH:19]=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=CC1=C(Br)CCCC1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=CC1=C(c2cccc([N+](=O)[O-])c2)CCCC1
Temperature: 25 °C
Yield: 73.7 %

Procedure:
Ethanol (11.1 mL) was added to a solution of 2-bromocyclohex-1-enecarbaldehyde (2.22 g) in toluene (22.2 mL). 3-Nitrophenylboronic acid (2.34 g), tetrakis(triphenylphosphine)palladium (270 mg) and a 1 N sodium carbonate solution (14.0 mL) were added to the mixture. The atmosphere of the reaction system was replaced with nitrogen. Then, the reaction solution was stirred with heating under reflux for three hours. The reaction solution was cooled to room temperature, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain the title compound (2.00 g).