Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:19][CH:18]([O:20][C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH2:17]3)=[O:15])=[N:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:29]([C:31]1([CH2:37][OH:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:29]([C:31]1([CH2:37][OH:38])[CH2:36][CH2:35][N:34]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH:18]3[CH2:19][N:16]([C:14]([C:12]4[O:13][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)=[N:10][N:11]=4)=[O:15])[CH2:17]3)=[CH:28][CH:27]=2)[CH2:33][CH2:32]1)[CH3:30]
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Reactant: CCC1(CO)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCC1(CO)CCN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccc(OC)cc5)o4)C3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-(5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde (0.55 g, 1.45 mmol in DCM (30 mL) were added (4-ethylpiperidin-4-yl)methanol (0.27 g, 1.88 mmol, 1.3 equiv) and sodium triacetoxyborohydride (0.615 g, 2.90 mmol, 2 equiv). The reaction mixture was stirred at room temperature overnight and thereafter transferred to a reparatory funnel, washed with a saturated solution of Na2CO3, dried (phase separator) and concentrated under reduced pressure. The crude product was purified by automatic flash column chromatography using Biotage (eluting with EtOAc (10 CV), then EtOAc/MeOH (containing 2 M NH3) 20:1) on a 50 g snap column, collecting at UV 291 nm). The pure product fractions were combined and evaporated to afford the product as a white solid. Recrystallisation from DCM/Et2O afforded 280 mg, 38% of the product as a white solid (purity >99%). 1H NMR (400 MHz, CDCl3): δ 0.82 (t, 3H), 1.37-1.56 (m, 6H), 2.30-2.46 (m, 4H), 3.45 (2×s, 4H), 3.89 (s, 3H), 4.33 (dd, 1H), 4.64 (dd, 1H), 4.74 (dd, 1H), 5.03-5.15 (m, 2H), 6.72 (d, 2H), 7.02 (d, 2H), 7.25 (d, 2H), 8.1 (d, 2H), MS (APCI+) m/z 507 [M+H]+.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([O:19][CH2:20][C:21]1[N:26]=[C:25]([C:27](O)=O)[CH:24]=[CH:23][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[CH2:11]([O:19][CH2:20][C:21]1[N:26]=[C:25]([CH2:27][N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N+:2]([O-:1])=[N:3]2)[CH:24]=[CH:23][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCOCc1cccc(C(=O)O)n1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCOCc1cccc(Cn2n[n+]([O-])c3ccccc32)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.1 %

Procedure:
To a suspension of 1-Hydroxybenzotriazole (0.283 g) and 6-octyloxymethylpicolinic acid (0.505 g) in dichloromethane (15 ml) was added 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (0.473 g), and stirred for 3 hours at ambient temperature. The reaction mixture was poured into water. The organic layer was taken, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-(6-Octyloxymethylpicolinyl)benzotriazole 3-oxide (737 mg).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16]([S:19]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH:31]=[O:32])[CH:29]=2)[CH:24]=[CH:23]1)(=[O:21])=[O:20])[CH2:17][CH3:18].[OH-].[K+].CO>O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]3[C:15]([CH:31]([C:28]4[CH:29]=[C:30]5[C:25]([CH:24]=[CH:23][N:22]5[S:19]([CH2:16][CH2:17][CH3:18])(=[O:21])=[O:20])=[CH:26][CH:27]=4)[OH:32])=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1cc2cc(OC3CCCC3)cnc2[nH]1
Reactant: CCCS(=O)(=O)n1ccc2ccc(C=O)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)n1ccc2ccc(C(O)c3c[nH]c4ncc(OC5CCCC5)cc34)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
Into a round bottom flask, was added 5-cyclopentyloxy-1H-pyrrolo[2,3-b]pyridine (P-0001, 0.110 g, 0.544 mol, prepared as describes in Example 12), 1-(propane-1-sulfonyl)-1H-indole-6-carbaldehyde (60, 0.169 g, 0.674 mol), potassium hydroxide (91.6 mg, 1.63 mol) and methanol (2 mL, 0.05 mol). The reaction was allowed to stir at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with a gradient of ethyl acetate (with 4% acetic acid) in hexanes to provide 88 mg of the desired compound. MS (EST) [M+H+]+=454.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Br:23])([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(N(C)C)=C(C)C.[N-:32]=[N+:33]=[N-:34].[Na+]>ClCCl.COC(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]([N:32]=[N+:33]=[N-:34])=[O:15])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Br:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2Br)CC1
Agent: CC(C)=C(Cl)N(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N=[N+]=[N-])(c2ccccc2Br)CC1
Reaction time: 0.75 h
Yield: 82.7 %

Procedure:
To a solution of 2.00 g (5.20 mmol) 4-(2-bromo-phenyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester in 26 ml dichloromethane were added 0.76 ml (5.73 mmol) 1-chloro-N,N,2-trimethylpropenylamine at room temperature. After stirring for 45 min the reaction mixture was concentrated in vacuo. The residual oil was redissolved in 26 ml dry N,N-dimethylformamide and treated with 0.51 g (7.8 mmol) sodium azide. After stirring for 1 h the reaction mixture was diluted with 200 ml tert-butyl methyl ether and washed with 0.5 M aqueous sodium carbonate solution (2×50 ml). The combined aqueous layers were extracted with tert-butyl methyl ether (2×100 ml). The combined organic layers were washed with water (1×50 ml) and brine (1×50 ml), dried over sodium sulfate and concentrated in vacuo to give the crude title compound (1.76 g, 83%) as a light yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[N:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1>CCCCCC>[CH2:1]([N:8]1[C:9]2=[N:13][C:14]3[C:15]([C:16]([NH2:17])=[C:10]2[CH2:11][CH2:12]1)=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccccc1N=C1CCCN1Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Nc1c2c(nc3ccccc13)N(Cc1ccccc1)CC2
Temperature: -10 °C
Yield: 37.9 %

Procedure:
The compound 1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-ylamine (Compound 25) was synthesized by first cooling a solution of Compound 24 (37.6 g, 0.14 mol) and tetrahydrofuran (350 mL) to −35° C. under argon atmosphere and adding a solution of hexane (110 mL) and lithium diisopropylamine-tetrahydrofuran complex (0.35 mol) dropwise. The temperature of the mixture was then gradually raised to −10° C. and ice-water (30 mL) was added dropwise. Organic solvent was evaporated under reduced pressure and the mixture was extracted with chloroform. The combined organic extracts were dried with anhydrous sodium sulfate and condensed under vacuum. The residue was treated with ethanol (15 mL) and crystals precipitated. The precipitate was filtered, washed with cold ethanol and dried under vacuum to yield 14.6 g (39%) of Compound 25 as needles; mp 174-176° C.; IR (KBr): 3411, 3116, 1654, 1502, 1350, 756 cm−1; 1H NMR (DMSO-d6): δ 7.01-7.93 (m, 9H), 6.05 (s, 2H), 4.60 (s, 2H), 3.37 (t, 2H), 2.87 (t, 2H); 13C NMR (CDCl3): δ 162.7, 149.3, 144.8, 138.8, 128.7, 128.2, 128.1, 127.2, 126.2, 121.8, 119.9, 117.6, 100.7, 48.4, 23.3. Anal. Calcd. for C18H17N3(275.35): C, 78.52; H, 6.22; N, 15.26. Found: C, 78.07; H, 6.07 N, 15.08;
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[S:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH2:34]O>C1(C)C=CC=CC=1>[N:15]([CH2:34][C:30]1[S:29][CH:33]=[CH:32][N:31]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1nccs1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
Diphenylphosphoryl azide (3.25 mL, 0.015 mol) and 1,8-diazabicyclo[5.4.0] undec-7-ene (2.25 mL, 0.025 mol) were added to a solution of thiazol-2-yl-methanol (1.44 g, 0.013 mol) in toluene (20 mL) at 0° C. After 1 hour, the reaction was warmed to room temperature and stirred overnight. The mixture was diluted with toluene (20 mL) and washed with H2O (3×) brine (1×), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (30% ethyl acetate/hexanes) to afford the azide as a tan oil (1.1 g, 63%). IR: 2098 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[N:17][N:16]([CH3:19])[C:15]=3[CH:20]=2)=[C:6]([CH:9]=1)[CH2:7]O.N1C=CC=CC=1.S(Cl)([Cl:29])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[N:17][N:16]([CH3:19])[C:15]=3[CH:20]=2)=[C:6]([CH2:7][Cl:29])[CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1nnc2ccc(Cc3ccc(Cl)cc3CO)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1nnc2ccc(Cc3ccc(Cl)cc3CCl)cc21
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To the solution of 5-chloro-2-[(1-methyl-1H-benzotriazole-6-yl)methyl]benzyl alcohol (0.16 g) from Example 77 and pyridine (0.05 ml) in methylene chloride (2 ml) was added thionyl chloride (0.04 ml) at 0° C., the mixture was stirred for 30 minutes. After removal of the solvent, the resulting residue was purified by chromatography on a silica gel column (methylene chloride:methanol=199:1), to give the title compound (0.12 g; 70%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH2:21]([N:23]1[CH2:29][CH2:28][C:27]2[CH:30]=[C:31]([NH2:34])[CH:32]=[CH:33][C:26]=2[CH2:25][CH2:24]1)[CH3:22].Cl.C(=O)([O-])[O-]>COCCO.O1CCOCC1>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:34][C:31]2[CH:32]=[CH:33][C:26]3[CH2:25][CH2:24][N:23]([CH2:21][CH3:22])[CH2:29][CH2:28][C:27]=3[CH:30]=2)=[N:3][CH:4]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCO
Solvent: C1COCCO1
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc2CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 28.1 %

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (99 mg, 0.29 mmol) was added into a vial, followed by a solution of 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (55.0 mg, 0.289 mmol) in 2-Methoxyethanol (3 mL). 4 M of Hydrogen chloride in 1,4-Dioxane (0.10 mL) was added and the reaction was heated at 120° C. After overnight stirring, Macroporous carbonate resin (3.16 mmol/g loading; 150 mg, 0.474 mmol) was added and the reaction was cooled to room temperature, then was concentrated in vacuo onto Celite, and chromatographed (14 g ISCO Amine column, DCM) to isolate N-{(1R,2R)-2-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo-[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}methane-sulfonamide as a beige foam (40 mg, 28%). LCMS (m/e) 493 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.92 (s, 1H), 7.24 (m, 2H), 7.04 (d, 1H, J=8.8 Hz), 6.76 (s, 1H), 5.38 (d, 1H, J=7.6 Hz), 5.28 (s, 1H), 3.87 (m, 1H), 3.22 (m, 1H), 2.91 (m, 4H), 2.77 (s, 3H), 2.64 (m, 3H), 2.57 (t, 2H, J=7.0 Hz), 2.21 (m, 2H), 1.82 (m, 2H), 1.37 (m, 4H), 1.10 (t, 3H, J=7.0 Hz).
Reaction SMILES: [BrH:1].[C:2]([O:5][CH2:6][C:7]1([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:16][CH:11](OC(=O)C)[C@H:10]([O:17][C:18](=[O:20])[CH3:19])[C@@H:9]([O:21][C:22](=[O:24])[CH3:23])[C@H:8]1[O:25][C:26](=[O:28])[CH3:27])(=[O:4])[CH3:3]>C(O)(=O)C>[C:2]([O:5][CH2:6][C:7]1([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:16][C@@H:11]([Br:1])[C@H:10]([O:17][C:18](=[O:20])[CH3:19])[C@@H:9]([O:21][C:22](=[O:24])[CH3:23])[C@H:8]1[O:25][C:26](=[O:28])[CH3:27])(=[O:4])[CH3:3]
Reactant: CC(=O)OCC1(COC(C)=O)OC(OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Br
Solvent: CC(=O)O
Product: CC(=O)OCC1(COC(C)=O)O[C@@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Glacial acetic acid (60 ml) is saturated with dry gaseous HBr for 30 minutes at 18°-20° C. This solution is mixed with 5-C-acetoxymethyl-1,2,3,4,6-penta-O-acetyl-L-arabino-hexopyranose (7) (6.0 g, 0.013 ml) and is stirred at an ambient temperature for 3.5 hours. Workup of the reaction mixture involves: dilution with methylene chloride (150 ml), washing with ice-water, sat. sodium bicarbonate solution, and water again. After drying the methylene chloride solution with sodium sulfate (anhydrous), evaporation of the solvent produces crude 5-C-acetoxymethyl-2,3,4,6-tetra-O-acetyl-α-L-arabino-hexopyranosyl bromide (18) (3 g) which is dried under high vacuum for 30 minutes and is used for the glycosidation reactions without further purification.
Reaction SMILES: [NH2:1][N:2]1[C:6]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]1=[NH:12].[O:13]1C[CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.C(Cl)(=O)CC>O>[NH2:1][N:2]1[C:6]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]1=[N:12][C:14](=[O:13])[CH2:15][CH3:16]
Reactant: Cc1cccc2sc(=N)n(N)c12
Reactant: C1CCOC1
Agent: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)N=c1sc2cccc(C)c2n1N

Procedure:
A 3.6 g. portion of 3-amino-2-imino-4-methylbenzothiazoline was dissolved in about 100 ml. of tetrahydrofuran, and 2.2 g. of triethylamine was added. The reaction mixture was cooled in an ice bath, and 2 g. of propionyl chloride, dissolved in 2 ml. of tetrahydrofuran, was added dropwise while the mixture was stirred. After the addition was complete, the reaction mixture was stirred at ice bath temperature for about 3 hours, and was then diluted with an equal volume of water. The tetrahydrofuran was removed under vacuum, and the remaining aqueous mixture was filtered to recover the product. After recrystallization from ethanol, the yield of purified product was 3.2 g. of 3-amino-4-methyl-2-propionyliminobenzothiazoline, m.p. 175°-76° C. The product was identified by nuclear magnetic resonance and ultraviolet analysis and by elemental microanalysis.
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:14][C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][C:17](=[O:18])[C:12]=2[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9]2)[CH:2]=[CH2:3].[H][H]>C(O)C.[Pd]>[O:18]=[C:17]1[CH:16]=[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:14][C:13]2[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]3[C:10](=[CH:11][C:12]1=2)[CH2:9][CH2:8][CH2:7][CH2:6]3
Reactant: [H][H]
Reactant: C=CCc1c2c(cc3c(=O)cc(C(=O)OCC)oc13)CCCC2
Agent: [Pd]
Solvent: CCO
Product: CCCc1c2c(cc3c(=O)cc(C(=O)OCC)oc13)CCCC2
Yield: 49.7 %

Procedure:
A solution of the product of step (a) (20 g), in ethanol (120 ml), was treated with a 5% palladium on charcoal catalyst (100 mg), and shaken in a hydrogen atmosphere at 45 psi for 2 hours at room temperature. The catalyst was subsequently filtered off and the filtrate was evaporated. The residue solidified upon trituration with a little diethyl ether and the solid was twice crystallised from aqueous ethanol to give as white crystals, ethyl 6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate (10 g), mp 98°-99.5°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([OH:11])[C:5]2=[C:4]([CH3:12])[CH:3]=1.[N:13]([C@@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)=[C:14]=[O:15]>C1COCC1.CN(C=O)C>[C@@H:16]1([NH:13][C:14]([N:9]2[C:10](=[O:11])[C:5]3[C:6](=[N:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:12])[NH:8]2)=[O:15])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: Cc1cc(Cl)nc2[nH]nc(O)c12
Reactant: O=C=N[C@H]1CCc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(Cl)nc2[nH]n(C(=O)N[C@H]3CCc4ccccc43)c(=O)c12

Procedure:
In analogy to example 1c, 200 mg (1.089 mmol) of 6-chloro-4-methyl-1H-pyrazolo-[3,4-b]pyridin-3-ol were reacted with 208.1 mg (1.2 mmol) of (S)-1-isocyanatoindane in THF/DMF at RT. Yield: 153 mg (41%), M+H+: 343.32.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][CH:3]=1.[Si](OC1C=CC(N)=CC=1)(C(C)(C)C)(C)C.[NH2:31][C:32]1[N:36]([CH3:37])[N:35]=[C:34]([C:38]#[N:39])[CH:33]=1>>[Si:7]([O:6][C:5]1[CH:14]=[CH:15][C:2]([NH:31][C:32]2[N:36]([CH3:37])[N:35]=[C:34]([C:38]#[N:39])[CH:33]=2)=[CH:3][CH:4]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Reactant: Cn1nc(C#N)cc1N
Agent: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Product: Cn1nc(C#N)cc1Nc1ccc(O[Si](C)(C)C(C)(C)C)cc1

Procedure:
The procedure is in accordance with the protocol of Step B of Preparation 1″, replacing the 4-bromo-1-methyl-1H-pyrazole by (4-bromophenoxy)-(tert-butyl)dimethyl-silane and the 4-{[tert-butyl(dimethyl)silyl]oxy}aniline by the compound from Step A.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:24])[N:5]([CH3:23])[C:6]1[N:7]2[CH:12]=[N:13][C:14]=1[C:15]1[N:19]=[C:18]([CH:20]2[CH2:22][CH2:21]2)[O:17][N:16]=1.[C-:25]#[N:26].[Na+]>CN(C)C=O.O>[C:25]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:24])[N:5]([CH3:23])[C:6]1[N:7]2[CH:12]=[N:13][C:14]=1[C:15]1[N:19]=[C:18]([CH:20]2[CH2:22][CH2:21]2)[O:17][N:16]=1)#[N:26]
Reactant: [C-]#N
Reactant: Cn1c(=O)c2c(Br)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(C#N)cccc2n2cnc(-c3noc(C4CC4)n3)c12

Procedure:
To 140 mg 6-bromo-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)4,5-dihydro-4-methyl-5-oxo-imidazo(1,5-a)quinazoline in 5 ml dimethyl formamide (DMF) 40 mg cuprous cyanide was added. Thereafter further 5 ml DMF was added and the resulting mixture was heated to 130°-150° C. for 60 minutes with stirring. To this mixture 110 mg sodium cyanide in 5 ml water was added and thereafter further 30 ml water. The resulting mixture was extracted with 30 ml ethyl acetate and thereafter four times with 20 ml ethyl acetate. The combined organic phase was washed with water and dried with calcium chloride. Evaporation in vacuo gave 24 mg of the title compound. M.p. 115°-125° C.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:11][CH:10]=2)[N:7]=[N:6][C:5]=1[C:21]([OH:23])=O)[CH2:2][CH3:3].C1C=C[C:27]2N(O)N=[N:30][C:28]=2[CH:29]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:28]1([NH:30][C:21]([C:5]2[N:6]=[N:7][N:8]([C:9]3[CH:10]=[CH:11][C:12]([C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:13][CH:14]=3)[C:4]=2[CH2:1][CH2:2][CH3:3])=[O:23])[CH2:29][CH2:27]1
Reactant: On1nnc2ccccc21
Reactant: CCCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCC)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.8 %

Procedure:
5-Propyl-1-{4-[(propylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxylic acid (498 mg, 1.57 mmol) obtained in Example 55b), HOBt (215 mg, 1.57 mmol, 1.0 eq.) and cyclopropylamine (0.146 ml, 2.05 mmol, 1.3 eq.) were dissolved in acetonitrile (4 ml) and DMF (4 ml), WSC (370 mg, 1.89 mmol, 1.2 eq.) was added and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), and washed with 5% aqueous sodium hydrogen carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (2:1, 20 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (542 mg, 1.52 mmol, 97.1%).
Reaction SMILES: [Cl: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](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([CH3:36])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:35][CH2:34][C@@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=1)=[O:22])[CH3:36]
Reactant: C[C@H](N)CO
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.20 g, 0.44 mmol), (S)-2-aminopropan-1-ol (0.10 ml, 1.31 mmol), HBTU (331 mg, 0.87 mmol), and HOBT (134 mg, 0.87 mmol). Then added DMF (1 mL) followed by N,N-diisopropylethylamine (0.31 mL, 1.75 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/hexanes (gradient: 0-100% EtOAc) to afford 149 mg (66%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21].[H-].[Na+].I[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1.C(OCC)(=O)C.Cl>[CH3:18][C:6]1[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]2[C:4]([C:5]=1[CH2:19][C:20]([NH2:22])=[O:21])=[CH:3][C:2]([O:1][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:10][CH:9]=2
Reactant: Ic1ccccc1
Reactant: Cc1c(CC(N)=O)c2cc(O)ccc2n1Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1c(CC(N)=O)c2cc(Oc3ccccc3)ccc2n1Cc1ccccc1
Reaction time: 0.17 h
Yield: 3 %

Procedure:
5-Hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide (1.2 g, 4.1 mmol) was dissolved in 40 mL of pyridine, 90 mg (2.2 mmol) of 60% NaH/mineral oil added, stirred 0.17 hours, 315 mg of CuO added, stirred 0.17 hours and 0.5 (4.1 mmol) mL of iodobenzene added. The mixture was heated to maintain reflux for 24 hours, cooled, and diluted with ethyl acetate and 1N HCl. The mixture was filtered thru a celite pad and the organic material separated, washed with brine, dried (Na2SO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted with 1% MeOH/methylene chloride→3% MeOH/methylene chloride to give 40 mg (3% yield) of 2-methyl-5-phenoxy-1-(phenylmethyl)-1H-indole-3-acetamide.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](N)=[O:8])=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)O.[CH2:17]([OH:19])[CH3:18]>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:19][CH2:17][CH3:18])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCO
Reactant: N#Cc1ccc(C(N)=O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(C#N)cc1
Yield: 75.9 %

Procedure:
p-Cyanobenzamide (73.0 g, 0.5 mol) which has a purity of 99% or more and ethanol (657.0 g) were placed in a 2 l-separable flask, and the mixture was allowed to react at 78° C. for 19 hours while a 95% sulfuric acid (51.6 g) was added thereto with stirring. Gas chromatographic analysis revealed that the reaction mixture contained 66.5 g of ethyl p-cyanobenzoate (yield 76%).