Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34]C(=O)OCC3C=CC=CC=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45]=[O:46])=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=O)(C)(C)C.Br.[CH3:48][C:49](O)=O>C1COCC1.C1([Mg]Br)C=CC=CC=1.CCOC(C)=O.Cl>[NH2:34][C:33]1[C:24]([C:22]([NH:21][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10]2)=[O:23])=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([CH:45]([OH:46])[C:49]1[CH:48]=[CH:13][CH:14]=[CH:9][CH:10]=1)[CH:27]=2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc3cc(C=O)ccc3cc2NC(=O)OCc2ccccc2)C1
Reactant: CC(=O)O
Agent: Br
Agent: Br[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cc2ccc(C(O)c3ccccc3)cc2nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of benzyl (2-{[(4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-formylquinolin-3-yl)carbamate (0.020 g, 0.032 mmol) (from Example 15, step 5) in THF (0.50 mL), phenylmagnesium bromide in THF (3.0 M, 0.032 mL, 0.096 mmol) was added slowly at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature. The reaction mixture was diluted with EtOAc (10 mL), and 1 M HCl was slowly added to adjust the pH to 7. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in DCM (1 mL) and HBr in AcOH (8.0 M, 1.0 mL, 8.0 mmol) was added. The resulting reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. To the residue was added 1 M NaOH, and the aqueous layer was extracted with DCM. The combined organic extracts were dried, filtered and concentrated under reduced pressure. The resulting crude product was purified by preparative LC-MS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with NH4OH) to give the title compound. LCMS calc. for C27H29N6O2 (M+H)+: m/z=469.3. Found: 469.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH:15](O)[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.N12CCCN=C1CCCCC2>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10](=[CH:15][CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC=C1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of 1.86 g (7.6 mmol) of the resulting 1-(t-butoxycarbonyl)-3-(1-hydroxyethyl)-4-piperidone in 20 ml of methylene chloride, 0.77 g (7.6 mmol) of triethylamine were added. To the resulting mixture, 0.88 g (7.6 mmol) of methanesulfonyl chloride were added under ice cooling, followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue and the solid so precipitated was filtered off, followed by concentration by evaporation under reduced pressure. The concentrate was then dissolved in 20 ml of chloroform. To the resulting solution, 1.16 g (7.6 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added at room temperature, followed by stirring at the same temperature for 2 hours. After the completion of the reaction, the reaction mixture was concentrated by evaporation under reduced pressure and the residue was subjected to chromatography on a silica gel column (eluting solvent: toluene/ethyl acetate=19/1), whereby 1.32 g (yield: 77.2%) of the title compound was obtained as a colorless oil.
Reaction SMILES: CN(C)CCNC.[Li]CCCC.[Cl:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[C:17]([CH:22]=[O:23])=[CH:16][CH:15]=1.[I:24]I>COCCOC>[Cl:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[C:17]([CH:22]=[O:23])=[C:16]([I:24])[CH:15]=1
Reactant: COc1nc(Cl)ccc1C=O
Reactant: II
Agent: CNCCN(C)C
Agent: [Li]CCCC
Solvent: COCCOC
Product: COc1nc(Cl)cc(I)c1C=O
Temperature: -23 °C
Reaction time: 0.33 h
Yield: 51.3 %

Procedure:
To a solution of N,N,N'-trimethylethylenediamine (2.46 mL, 19.23 mmol) in 15 mL of 1,2-dimethoxyethane at -23° C. was added n-BuLi (9.22 mL, 19.23 mmol), and the solution was stirred at -23° C. for 20 min. The mixture was transferred using a double-tipped needle to a solution of 6-chloro-2-methoxy-3-pyridinecarboxaldehyde (3.0 g, 17.5 mmol) in 40 mL of 1,2-dimethoxyethane at -23° C. After stirring for 15 min, n-BuLi (12.6 mL, 26.2 mmol) was added and the dark mixture was stirred an additional 2 h at -23° C. The solution was transferred using a double-tipped needle to a solution of iodine (8.04 g, 31.7 mmol) in 40 mL of 1,2-dimethoxyethane at -78° C. After stirring at -78° C. for 30 min, the cooling bath was removed and the reaction mixture was allowed to warm for 20 min, then quenched with water. The mixture was extracted with ether (2×30 mL) and the combined organic layers were washed successively with 30-mL portions of 10% aqueous Na2S2O3, water and brine, and dried over MgSO4. Concentration afforded 4.62 g (89%) of crude product to which was added 50 mL of hexanes. The mixture was stirred and allowed to stand at 5° C. overnight. Filtration gave 2.67 g of 6-Chloro-4-iodo-2-methoxy-3-pyridinecarboxaldehyde as a yellow solid: mp 120°-124° C. Concentration of the hexane washings and purification of the residue by radial preparative thin-layer chromatography (silica gel, 5% ethyl acetate/hexanes) gave an additional 1.41 g of product (mp 120°14 124° C.), raising the total yield of the compound to 78%. Recrystallization from hexanes gave an analytical sample as a bright yellow solid: mp 129°-130° C. 1H NMR (300 MHz, CDCl3) δ10.16 (s, 1H), 7.59 (s, 1H), 4.07 (s, 1H): IR (nujol) 1690, 1350, 1260, 1095, 1010, 900, 840 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:6].[CH3:22][O:23][C:24](=[O:37])[CH2:25][O:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH:34]=O)=[C:29]([CH3:36])[CH:28]=1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>CS(C)=O.CCOC(C)=O>[CH3:22][O:23][C:24](=[O:37])[CH2:25][O:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([C:34]2[NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)[CH:18]=[CH:19][C:20]=3[N:21]=2)=[C:29]([CH3:36])[CH:28]=1
Reactant: COC(=O)COc1cc(C)c(C=O)c(C)c1
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)COc1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,4-diamino-N-quinolin-2-yl-benzamide (770 mg, 2.77 mmol) and (4-formyl-3,5-dimethylphenoxy)-acetic acid methyl ester (615 mg, 2.77 mmol) in DMSO (10 mL) was added Yb(OTf)3 (344 mg, 0.55 mmol) and the mixture was stirred at ambient temperature overnight. The reaction mixture was partioned between water and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered and concentrated. Purification by flash chromatography using heptane/EtOAc (1:4) as eluent gave {3,5-dimethyl-4-[6-(quinolin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-phenoxy}-acetic acid methyl ester as a white solid. MS (m/z) 481.4 (M+1); 1H NMR (Methanol-d4, 400 MHz): δ 8.45 (m, 3H), 8.04 (d, 1H), 7.92 (d, 2H), 7.75 (m, 2H), 7.54 (m, 1H), 6.80 (s, 2H), 4.78 (s, 2H), 3.81 (s, 3H), 2.17 (s, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]=1[CH3:9])(=[O:3])[CH3:2].[ClH:16].Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[CH2:30]=O>C(O)C>[ClH:16].[ClH:16].[CH3:9][C:8]1[N:7]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:6]=[CH:5][C:4]=1[C:1](=[O:3])[CH2:2][CH2:30][N:27]1[CH2:28][CH2:29][N:24]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:18]=2)[CH2:25][CH2:26]1
Reactant: CC(=O)c1cnn(-c2ncccn2)c1C
Reactant: C=O
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Solvent: CCO
Product: Cc1c(C(=O)CCN2CCN(c3ncccn3)CC2)cnn1-c1ncccn1
Yield: 72.5 %

Procedure:
404 mg of 4-acetyl-1-(2-pyrimidinyl)-5-methylpyrazole and 474 mg of 1-(2-pyrimidinyl)piperazine dihydrochloride were dissolved in 15 ml of ethanol and heated under reflux for 23 hours. During this period, 900 mg of paraformaldehyde was added thereto in portions. The reaction mixture was cooled, and the precipitate thus formed was taken up by filtration and washed with methanol. Thus 327 mg of the title compound was obtained in the form of a colorless solid product.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C:31](=[O:37])[C@@H:30]([OH:38])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C:31](=[O:37])[C:30](=[O:38])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4C(=O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4C(=O)C(=O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
Using the procedure described in Org. Syn., 1976, 55, 84, (3β,5α,12β,25R)-3-(t-butyldimethyisilyloxy)-spirostan-12-ol-11-one was oxidized with chromium trioxide and pyridine in methylene chloride to give the title compound.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=2)=[C:6]([C:16]#[N:17])[C:5]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])(=[O:3])[CH3:2].OI(C1C=CC=CC=1)[O:28][S:29]([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30].C(#N)C>>[CH3:36][C:35]1[CH:34]=[CH:33][C:32]([S:29]([O:31][CH2:2][C:1]([C:4]2[S:8][C:7]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=3)=[C:6]([C:16]#[N:17])[C:5]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[O:3])(=[O:30])=[O:28])=[CH:38][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Reactant: CC(=O)c1sc(-c2ccnc(F)c2)c(C#N)c1-c1ccc(Cl)cc1Cl
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCC(=O)c2sc(-c3ccnc(F)c3)c(C#N)c2-c2ccc(Cl)cc2Cl)cc1
Temperature: 90 °C
Yield: 46 %

Procedure:
A mixture of 5-acetyl-4-(2,4-dichlorophenyl)-2-(2-fluoropyridin-4-yl)thiophene-3-carbonitrile (0.48 g, 1.2 mmol) and [hydroxy(tosyloxy)iodo]benzene (0.819 g, 2.09 mmol) in ACN (20 mL, 400 mmol) was heated at 90° C. overnight. The mixture was cooled down to rt. The solvent was evaporated and the residue was purified by column chromatography to afford the title compound (0.31 g, 45%). NMR (300 MHz, d1-chloroform) δ: 8.44 (1H, d, J=5.27 Hz), 7.69 (2H, d, J=8.34 Hz), 7.62 (2H, ddd, J=6.91, 3.43, 1.72 Hz), 7.47 (1H, dd, J=8.25, 2.02 Hz), 7.39-7.33 (3H, m), 7.30 (1H, d J=5.79), 4.47 (2H, s), 2.47 (3H, s)
Reaction SMILES: [ClH:1].[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].[S:14]([O-:18])([O-:17])(=[O:16])=[O:15].[Li+:19].[Li+]>O>[Cl-:1].[Li+:19].[S:14]([OH:18])([OH:17])(=[O:16])=[O:15].[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5]
Reactant: O=S(=O)([O-])[O-]
Reactant: Cl
Agent: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: [Li+]
Solvent: O
Product: O=S(=O)(O)O
Product: [Cl-]

Procedure:
Example 1 was repeated using 1679 g of purified water, 431.5 g (2 moles) of glucosamine hydrochloride and 128 g (1 mole) of lithium sulfate (monohydrate) instead of the sodium sulfate. After freeze drying, glucosamine sulfate lithium chloride was obtained as a white powder in a yield of 525 g (97% of theoretical).
Reaction SMILES: [N:1]([CH:4]1[CH2:19][CH2:18][C:7]2=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:9][C:10]([S:11][CH3:12])=[C:6]2[C:5]1=[O:20])=[N+]=[N-].[C:21](OC(=O)C)(=[O:23])[CH3:22]>[C].[Pd].C(O)(=O)C>[C:21]([NH:1][CH:4]1[CH2:19][CH2:18][C:7]2=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:9][C:10]([S:11][CH3:12])=[C:6]2[C:5]1=[O:20])(=[O:23])[CH3:22]
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(N=[N+]=[N-])C2=O
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(SC)c2c1CCC(NC(C)=O)C2=O
Yield: 73.8 %

Procedure:
A mixture of ethyl 5-azido-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo(c]thiophene-1-carboxylate (3.62 g), palladium-carbon (5%, 50% wet, 4.0 g), acetic acid (70 ml) and acetic anhydride (35 ml) was subjected to a catalytic reduction reaction at room temperature under 1 atm. The insoluble substances were filtered off; the filtrate was concentrated under reduced pressure; the residue was dissolved in ethyl acetate-tetrahydrofuran (3:1, v/v). This solution was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and dried (MgSO4), after which the solvent was distilled off to yield ethyl 5-acetylamino-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (2.81 g, 73.8%), which was then recrystallized from chloroform-ethanol. Colorless needles. Melting point 215-216° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:15]=[N:14][C:13]2[C:12]3=[N:16][N:17]=[CH:18][N:11]3[C:10](=[O:19])[NH:9][C:8]1=2.C(=O)([O-])[O-].[K+].[K+].[CH2:26](I)[CH:27]([CH3:29])[CH3:28]>CN(C=O)C.O>[CH2:26]([N:9]1[C:8]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH:15]=[N:14][C:13]=2[C:12]2=[N:16][N:17]=[CH:18][N:11]2[C:10]1=[O:19])[CH:27]([CH3:29])[CH3:28]
Reactant: O=c1[nH]c2c(ncn2C2CCCCO2)c2nncn12
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(=O)n2cnnc2c2ncn(C3CCCCO3)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-(tetrahydro-2h-pyran-2-yl)-6,7-dihydro-5h-[1,2,4]triazolo[3,4-i]purin-5-one (2.08 g, 4.0 mmol) in DMF (20 ml), was added potassium carbonate (1.10 g, 8.0 mmol) and isobutyl iodide (1.47 g, 8.0 mmol). The mixture was stirred at room temperature overnight. The reaction was diluted with water and extracted with EtOAc three times. The combined organic layers was dried with sodium sulfate, filtered, and concentrated in vacuo to give the product. LCMS calculated for C15H21N6O2(M+H): 317.2. found: 317.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[NH:15][C:16]([CH2:23][CH2:24][C:25](O)=O)=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19][CH2:18]2.Cl[C:29]1[CH:34]=[CH:33][C:32](C2CCNCC2)=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:24][CH2:23][C:16]3[N:15]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:14]=[C:22]4[C:17]=3[CH2:18][CH2:19][CH2:20][CH2:21]4)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Product: Clc1ccc(N2CCN(CCCc3c4c(nn3-c3ccccc3)CCCC4)CC2)cc1

Procedure:
In the same manner as in Example 102 except that 3-(4,5,6,7-tetrahydro-2-phenyl-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 11 and 1-(4-chlorophenyl)piperazine were used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2-phenyl-2H-indazole was obtained, m.p. 127-129° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]([C:19]2[C:20]3[N:21]([N:26]=[CH:27][N:28]=3)[C:22](Br)=[CH:23][N:24]=2)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:6]=1)[CH3:2].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][NH:41][CH:42]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:19]2[C:20]3[N:21]([N:26]=[CH:27][N:28]=3)[C:22]([C:38]3[CH:39]=[N:40][NH:41][CH:42]=3)=[CH:23][N:24]=2)[CH:6]=1)[CH3:2]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCOC(=O)c1cccc(N(C(=O)OC(C)(C)C)c2ncc(Br)n3ncnc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cccc(N(C(=O)OC(C)(C)C)c2ncc(-c3cn[nH]c3)n3ncnc23)c1
Temperature: 115 °C
Yield: 108.6 %

Procedure:
Nitrogen is bubbled through a mixture of 3-[(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-tert-butoxycarbonyl-amino]benzoic acid ethyl ester (0.58 g, 1.25 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.49 g, 2.50 mmol), K2CO3 (0.35 g, 2.50 mmol) and Pd(dppf)Cl2DCM (102 mg, 0.125 mmol) in dioxane (37.5 mL) and water (9.6 mL). A condenser is fitted to the flask, the system is evacuated and purged with N2 (g) and then heated at 115° C. for 25 min. The heating bath is removed and CO2 (s) is added to cool and buffer the system. The solvent is removed under reduced pressure and the residue is purified by silica chromatography, eluting with 10% to 50% ethyl acetate in DCM, to afford the title compound as an orange oil (0.61 g, >100%) which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:7]=1.Cl.[O:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:33][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c2c(Cl)nc(Cl)nc21
Reactant: NC1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c2c(NC3CCOCC3)nc(Cl)nc21
Temperature: 120 °C
Yield: 34 %

Procedure:
To a solution of 2,4-dichloro-5-(pyridin-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv) in 1,4-dioxane (0.4 M) in a sealable vessel was added tetrahydro-2H-pyran-4-amine hydrochloride (1.5 equiv) and triethylamine (3 equiv). The resulting mixture was heated at 120° C. for 2 h under nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate in petroleum ether) to afford the desired product (34% yield) as a yellow solid. MS (ESI) m/z 460.2 [M+1]+.
Reaction SMILES: C([C@@H]([C@H](C(O)=O)O)O)(O)=O.[CH3:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[CH3:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1
Reactant: C[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(2R)-2-Methylpyrrolidine L-tartrate (4.0 g, 17.0 mmol), 1-(2-bromoethyl)-4-nitrobenzene (9.8 g, 43 mmol), and potassium carbonate (12 g, 85 mmol), were combined in DMF (20 mL) in a sealed tube at 50° C. and stirred vigorously for 16 hours. The mixture was allowed to cool to room temperature, diluted with diethyl ether (100 mL), washed with water (2 times, 100 mL and then 50 mL), and extracted with 1 M HCl (2 times, 50 mL and 25 mL). The aqueous acidic extractions were combined, washed with diethyl ether (50 mL), cooled to 0° C., adjusted to pH 14 with 50% NaOH solution, and extracted with dichloromethane (3 times, 50 mL). The dichloromethane extractions were combined, dried (MgSO4), filtered, and the filtrate concentrated to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 1.08 (d, J=6 Hz, 3 H), 1.43 (m, 1 H), 1.75 (m, 2 H), 1.93 (m, 1 H), 2.19 (q, J=9 Hz, 1 H), 2.34 (m, 2 H), 2.91 (m, 2 H), 3.03 (m, 1 H), 3.22 (td, J=8, 3 Hz, 1 H), 7.38 (d, J=9 Hz, 2 H), 8.15 (d, J=9 Hz, 2 H); MS (DCl/NH3) m/z 235 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]([OH:5])[CH2:3][CH3:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.N1C=CC=CC=1.ClCCl>CN(C)C1C=CN=CC=1.O>[CH3:1][C@@H:2]([OH:5])[CH2:3][CH3:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O-:15])(=[O:5])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: CC[C@@H](C)O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=S(=O)([O-])c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67 %

Procedure:
A mixture of 8.2 g of (R)-(−)2-butanol, 31.5 g of 1-bromo-4-benzenesulfonyl chloride, 1.0 g of N,N-dimethyl-4-pyridinamine, 55.5 ml of pyridine and 293 ml of dichloromethane was stirred for 3 days at room temperature. After the addition of water, stirring was continued for 1 hour. The reaction mixture was washed twice with a diluted hydrochloric acid solution and once with water, dried, filtered and evaporated in vacuo. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 11.5 g (35.6%) of (R)-2-butanol 4-bromobenzenesulfonate (ester) (interm. 3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[I:15]Cl.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[I:15][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: ClI
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(I)c(CC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
3,4-Dimethoxyphenylacetic acid (4.0 g, 20.4 mmol) was dissolved in 100 ml of glacial acetic acid. Iodine monochloride (1.35 eq, 1.38 ml) was added slowly and the mixture was allowed to stir at room temperature overnight. To the mixture was added 300 ml of a 10% aqueous solution of sodium bisulfite. The mixture was concentrated in vacuo to remove most of the acetic acid. The aqueous residue was extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether and the solid was then filtered and dried to give (2-iodo-4,5-dimethoxy-phenyl)-acetic acid (2.94 g, 44.8%) as an off-white solid.