Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(OCC)(=O)C>C1C=CC=CC=1>[CH:4]([C:5]1[S:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)=[CH:3][CH3:2]
Reactant: OCCCc1ccc(-c2cccs2)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: CC=Cc1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 g of 5-hydroxypropyl-2,2'-bithiophene was dissolved in 20 ml of benzene, followed by adding 0.1 g of p-toluene-sulfonic acid. The mixture was then stirred at room temperature for 2 hours while monitoring by thin layer chromatography. After completion of reaction, 30 ml of water and 100 ml of ethyl acetate were then added to the mixture. The ethyl acetate extract was further purified by column chromatography. The eluant was ethyl acetate/n-hexane (1/9). The slightly yellowish liquid product was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.OS(O)(=O)=O.[I:24](O)(=O)(=O)=O.II>C(O)(=O)C>[Cl:1][C:2]1[C:3]([I:24])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)ccc21
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(I)cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a stirred solution of 8-chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (1.0 g, 3.87 mmol) in acetic Acid (25 mL) was added H2SO4 (0.206 mL, 3.87 mmol) followed by periodic acid (0.881 g, 3.87 mmol). The mixture was then heated to 80° C. for 20 min. I2 (0.294 g, 1.160 mmol) was then added at 80° C. and stirred for 120 min. After cooling to ambient temperature, the acetic acid was removed under reduced pressure. The residue was neutralized with 70 mL of saturated aqueous sodium bicarbonate solution. The solid so obtained was collected by vacuum filtration and air dried to afford 8-chloro-9-iodo-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (1.3 g, 3.21 mmol, 83% yield) as a brown solid. LC/MS (ESI) m/e 385.1 [(M+H)+, calcd for C14H11ClIN2O 384.9]; LC/MS retention time (method E): tR=1.09 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.96 (s, 1H) 8.69 (d, J=5.58 Hz, 1H) 8.36 (d, J=5.52 Hz, 1H) 7.76 (s, 1H) 3.63 (s, 3H) 3.00 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([O-:21])=[O:20])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Yield: 73 %

Procedure:
To a solution of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylate prepared as set forth in Example A-224 (0.90 g, 0.003 mol) in 10 mL of ethanol was added a solution of sodium hydroxide (0.24 g, 0.006 mol) in 5 mL of water. The reaction mixture was heated at reflux for 10 hours. After the removal of solvent, the residue was dissolved in water and acidified with citric acid solution to pH 5. Then the aqueous phase was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate and concentrated. The crude was purified by treating with ether to give 0.62 g of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylic acid as a white solid (73% yield), mp: 245° C. (dec). Anal Calc'd for C15H10FN3O+0.2H2O: C, 62.80; H, 3.65; N, 14.65. Found: C, 62.77; H, 3.42; N, 14,58.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14](=[S:16])[NH2:15])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.Br[CH2:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21]>C(#N)C>[Br:1][C:2]1[C:3]([C:14]2[S:16][CH2:18][C:19]([OH:24])([C:20]([F:23])([F:22])[F:21])[N:15]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Solvent: CC#N
Product: CCNC(=O)Nc1cc(C2=NC(O)(C(F)(F)F)CS2)c(Br)cn1
Temperature: 80 °C
Yield: 96 %

Procedure:
A suspension of 5-bromo-2-(3-ethylureido)pyridine-4-carbothioamide (Intermediate 6, 160 g, 510 mmol), 3-bromo-1,1,1-trifluoroacetone (200 g, 1.02 mol) in acetonitrile (3 L) was heated at 80° C. for 20 h. The solution was then cooled down and concentrated. 2:1 Acetonitrile: methyl tert-butyl ether (2.4 L) was added, and the solution thus obtained was placed on a rotovap, and the volume of solvent was reduced by half. The precipitate that formed was filtered and dried in a vacuum oven at 40° C. After letting the filtrate sit, more solid precipitated out and an additional two crops of precipitate were collected and dried in the vacuum oven at 40° C. resulting in a combined collection of 202.4 g (92%) of 1-(5-bromo-4-(4-hydroxy-4-(trifluoromethyl)-4,5-dihydrothiazol-2-yl)pyridin-2-yl)-3-ethylurea as pale yellow solid.
Reaction SMILES: P(Cl)(Cl)(OP(Cl)(Cl)=O)=O.[N+:10]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)([O-:12])=[O:11].[C:22]([O:26]N1CCCC1C)(=[O:25])[CH:23]=[O:24].[C:33]([O-])(O)=O.[Na+]>CO>[N+:10]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15]([C:23](=[O:24])[C:22]([O:26][CH3:33])=[O:25])=[CH:16][NH:17]2)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: CC1CCCN1OC(=O)C=O
Reactant: O=C([O-])O
Agent: O=P(Cl)(Cl)OP(=O)(Cl)Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)c1c[nH]c2cccc([N+](=O)[O-])c12
Temperature: 25 °C

Procedure:
Diphosphoryl chloride (0.938 mL, 6.80 mmol) was added dropwise to a solution of 4-nitroindole (1.00 g, 6.17 mmol) and methylpyrrolidinyl glyoxylate (Downie et al., Tetrahedron, 1993, 49, 4015-4034) (1.10 g, 6.80 mmol) at 0° C. and the mixture was allowed to warm to ambient temperature over 3 h. MeOH, then saturated aqueous NaHCO3 were added to the reaction at 0° C. and the solution was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo until crystals formed. The crystals were collected by vacuum filtration and two more crops were isolated from the filtrate to give the title compound. MS: m/z=249 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16]C)[C:13]([O:18]C)=[C:12]([O:20]C)[CH:11]=2)=[CH:4][CH:3]=1.O>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][C:10]2[CH:15]=[C:14]([OH:16])[C:13]([OH:18])=[C:12]([OH:20])[CH:11]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(CSc2ccc(O)cc2)cc(OC)c1OC
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(SCc2cc(O)c(O)c(O)c2)cc1
Temperature: -78 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
3,4,5-Trimethoxybenzyl 4-hydroxyphenyl thioether (12 g, 39.2 mmol), prepared as described in Example 1, was dissolved in 240 ml of dry methylene chloride, and cooled to -78° C. A solution of borontribromide (18.6 ml, 195.6 mmol) in 60 ml of dry methylene chloride was added dropwise to the above solution. The mixture was warmed to room temperature, stirred overnight, cooled to 0° C., and added 300 ml of water. The aqueous layer was then extracted twice with 200 ml of ethyl acetate, dried over magnesium sulfate, concentrated and purified on silica gel column chromatography (ethyl acetate/n-hexane=2/1) to give 8.6 g (77% yield) of 3,4,5-trihydroxybenzyl 4-hydroxyphenyl thioether as a white powder.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[C:11]([F:13])[CH:12]=1.[C:19](=[O:21])=[O:20].CCOCC>C1COCC1>[F:6][C:7]1[CH:8]=[C:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[C:11]([F:13])[C:12]=1[C:19]([OH:21])=[O:20]
Reactant: O=C=O
Reactant: CCCCCc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCc1cc(F)c(C(=O)O)c(F)c1

Procedure:
A solution of n-butyllithium (10.5M in hexane; 2.70 ml, 0.028 mol) was added dropwise to a stirred, cooled (-78° C.) solution of compound 13 (5.10 g, 0.028 mol) in dry THF (30 ml) under dry nitrogen. The stirred mixture was maintained under these conditions for 2.5 h and then poured onto a slurry of solid carbon dioxide and dry ether. The product was extracted into 10% sodium hydroxide which was then acidified with 36% hydrochloric acid. The acidic mixture was washed with ether (twice), and the combined ethereal layers were washed with water and dried (MgSO4). The solvent was removed in vacuo to yield a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:16]=[CH:15]3)=[O:10])=[CH:4][CH:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:28]1([NH:1][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[N:16]=[CH:15]4)=[O:10])=[CH:4][CH:3]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc(NC(=O)Nc2ccc3c(cnn3CCN3CCCC3)c2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Nc2ccccc2)cc1)Nc1ccc2c(cnn2CCN2CCCC2)c1
Yield: 45.4 %

Procedure:
A mixture of 1-(4-amino-phenyl)-3-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-yl]-urea (364 mg, 1 mmol), phenylboronic acid (244 mg, 2 mmol), copper(II) acetate (364 mg, 2 mmol), triethylamine (0.2 mL, 2 mmol), in 20 mL of dichloromethane was refluxed overnight. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (acetonitrile/ethyl acetate/triethylamine, 10/4/1) to provide the title compound as a pale white solid (200 mg, 45%). 1H NMR (300 MHz, DMSO-d6) ppm 1.63 (m, 4H), 2.45 (m, 4H), 2.86 (d, J=6.44, 2H), 4.46 (d, J=6.44, 2H), 6.74 (m, 1H), 6.98 (m, 2H), 7.03 (m, 2H), 7.18 (m, 1H), 7.33–7.36 (m, 3H), 7.58 (m, 1H), 7.88 (m, 1H), 7.90 (s, 1H), 7.95 (s, 1H), 8.44 (s, 1H), 8.55 (s, 1H); MS (DCI/NH3) m/z 441 [M+H]+.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][NH2:8])([O-:4])=[O:3].[OH:13][CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:15][C:16](O)=[O:17].C(N(CC)CC)C.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.O.Cl>O1CCCC1>[OH:13][CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:15][C:16]([NH:8][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[N+:2]([O-:4])=[O:3])=[O:17]
Reactant: NCc1ccccc1[N+](=O)[O-]
Reactant: O=C(O)CC(O)c1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CC(O)c1ccccc1)NCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.1 %

Procedure:
2-Nitrobenzyl amine hydrochloride (2.27 g, 12.0 mmol), 3-hydroxy-3-phenyl propionic acid (2.00 g, 12.0 mmol), triethylamine (1.34 g, 13.3 mmol) were added to tetrahydrofuran (50 ml) and the reaction mixture was ice cooled. Under ice cooled condition, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (3.33 g, 12.0 mmol) was added thereto and stirred at room temperature for five hours. The reaction mixture was poured into dilute hydrochloric acid water and extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude crystal was washed with a mixture of hexane-ether (2:1) to obtain 3-hydroxy-N-(2-nitrobenzyl)-3-phenyl propionic acid amide (3.32 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4](Cl)[N:3]=1.[O:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.[C:36]([O-:39])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:13][N:9]1[C:10](=[O:12])[C:11]2[C:2]([C:24]3[CH:23]=[CH:22][C:21]([N:18]4[CH2:17][CH2:16][O:15][CH2:20][CH2:19]4)=[CH:26][CH:25]=3)=[N:3][C:4]([C:24]3[CH:25]=[CH:26][C:21]([N:18]4[CH2:19][CH2:36][O:39][CH2:16][CH2:17]4)=[CH:22][CH:23]=3)=[CH:5][C:6]=2[N:7]=[CH:8]1
Reactant: O=C([O-])[O-]
Reactant: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cnc2cc(-c3ccc(N4CCOCC4)cc3)nc(-c3ccc(N4CCOCC4)cc3)c2c1=O
Temperature: 140 °C

Procedure:
To a solution of 5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (23.0 mg, 0.10 mmol) in 1,4-dioxane (0.5 mL) were added 4-morpholinophenylboronic acid pinacol ester (57.8 mg, 0.20 mmol), 2M aqueous Na2CO3 solution (150 μL, 0.30 mmol), and a catalytic amount of Pd(PPh3)4. The reaction mixture was purged with N2 and heated at 140° C. by a microwave reactor for 15 minutes. The mixture was then cooled, quenched with H2O (5 mL) and extracted with ethyl acetate (3×2.5 mL). The combined organic layers were evaporated under vacuo and the residue was purified by preparatory LC/MS to provide the title compound; HPLC-MS calculated for C28H29N5O3 (M+H+) 484.2, found 484.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[Br:18][CH2:19][CH2:20][F:21]>CC(=O)C(C)(C)C>[Br-:18].[F:21][CH2:20][CH2:19][N+:15]1[CH:16]=[CH:17][C:12]([C:5]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:13][CH:14]=1
Reactant: COc1cc(-c2ccncc2)ccc1[N+](=O)[O-]
Reactant: FCCBr
Solvent: CC(=O)C(C)(C)C
Product: COc1cc(-c2cc[n+](CCF)cc2)ccc1[N+](=O)[O-]
Product: [Br-]
Temperature: 110 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To 4-[3-(methyloxy)-4-nitrophenyl]pyridine (Example 137, step A) (2.3 g, 10 mmol) in pinacolone (25 mL) is added 1-bromo-2-fluoroethane (2.5 g, 20 mmol). The mixture was stirred at 110° C. in a sealed tube overnight. The solution was cooled to rt and the solid collected by vacuum filtration washing with acetone. The title compound of step A (2.0 g, 5.6 mmol, 56%) was obtained as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ9.21 (d, J=7.0 Hz, 2H), 8.68 (d, J=7.3 Hz, 2H), 8.12 (d, J=8.4 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 7.77 (dd, J=8.4, 1.8 Hz, 1H), 5.05 (s, 2H), 5.00-4.90 (m, 2H), 4.07 (s, 3H). MS (ESI) m/z=277 [M].
Reaction SMILES: CN(C)C=O.[H-].[Na+].[C:8]([OH:11])(=[S:10])[CH3:9].CS(O[CH:17]1[CH2:21][CH2:20][N:19]([C:22](=[N:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])[CH3:23])[CH2:18]1)(=O)=O>O>[C:8]([S:10][CH:17]1[CH2:21][CH2:20][N:19]([C:22](=[N:24][C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)=[O:26])[CH3:23])[CH2:18]1)(=[O:11])[CH3:9]
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCC(OS(C)(=O)=O)C1
Reactant: CC(O)=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SC1CCN(C(C)=NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
To 300 ml of anhydrous N,N-dimethylformamide were added 7.35 g of sodium hydride in the form of a 55% w/w/ dispersion in oil, followed by 12.5 g of thioacetic acid. The mixture was then stirred for 10 minutes, with ice-cooling, after which 40 g of 3-methanesulphonyloxy-1-(N-p-nitrobenzyloxycarbonylacetimidoyl)pyrrolidine were added. The mixture was then stirred for 3 hours at 65° C. After the reaction mixture had been allowed to cool, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and dried and then the solvent was distilled off under reduced pressure. The residue was purified by chromatography through a column of silica gel, eluted with a 2:1 by volume mixture of benzene and ethyl acetate, to give 30 g of the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]2[C:24]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[NH:18][CH:17]=2)[CH2:9][CH2:8]1.CN(C)[CH:27]=[O:28]>>[CH3:6][N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][C:16]2[C:24]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[NH:18][C:17]=2[CH:27]=[O:28])[CH2:11][CH2:12]1
Reactant: CN(C)C=O
Reactant: CN1CCN(CCCc2c[nH]c3c2CCCC3)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
Phosphorus oxychloride (1.8 mL, 18.9 mmol) was added dropwise to cooled dimethylformamide (3.8 mL, 51.6 mmol). After stirring at room temperature for 30 minutes, it was cooled to −5° C. and a solution of 3-[3-(4-methyl-piperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole (4.5 g, 17.2 mmol) in dimethylformamide (9 mL) was added dropwise. The mixture was stirred at room temperature overnight. The reaction was quenched with ice, followed by 10 N sodium hydroxide to pH 10–11. After stirring at room temperature for 1 hour, the reaction was extracted with ethyl acetate, washed with brine, dried and concentrated to give 3.1 g (62% yield) of 3-[3-(4-methyl-piperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde. 1H-NMR (360 MHz, diemthylsulfoxide-d6) δ 11.24 (br, s, 1H, NH), 9.42 (s, 1H, CHO), 2.60 (t, 2H, CH2), 2.51 (m, 2H, CH2), 2.35 (m, 2H, CH2), 2.28 (m, 8H, 4×CH2), 2.21 (m, 2H, CH2), 2.12 (s, 3H, CH3), 1.57–1.68 (m, 6H, 3×CH2). MS m/z 289 [M+].
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:11]O)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.O=S(Cl)[Cl:15]>>[Cl:1][C:2]1[N:3]([CH2:11][Cl:15])[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.[ClH:1]
Reactant: O=S(Cl)Cl
Reactant: OCn1nc2ccccc2c1Cl
Product: Cl
Product: ClCn1nc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(3-chloro-2H-indazol-2-yl)methanol was dissolved in SOCl2 (10 mL). The mixture was stirred at room temperature for 3 hours and evaporated to provide crude 3-chloro-2-(chloromethyl)-2H-indazole as a HCl salt.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:15][O:16][C:17]1[C:31]([O:32][CH3:33])=[CH:30][C:20]2[NH:21][C:22]([C:24]3[C:28]([NH2:29])=[CH:27][NH:26][N:25]=3)=[N:23][C:19]=2[CH:18]=1.[F:34][C:35]1[CH:36]=[CH:37][C:38]([O:44][CH3:45])=[C:39]([CH:43]=1)[C:40](O)=[O:41]>CN(C=O)C>[CH3:33][O:32][C:31]1[C:17]([O:16][CH3:15])=[CH:18][C:19]2[NH:23][C:22]([C:24]3[C:28]([NH:29][C:40](=[O:41])[C:39]4[CH:43]=[C:35]([F:34])[CH:36]=[CH:37][C:38]=4[O:44][CH3:45])=[CH:27][NH:26][N:25]=3)=[N:21][C:20]=2[CH:30]=1
Reactant: COc1cc2nc(-c3n[nH]cc3N)[nH]c2cc1OC
Reactant: COc1ccc(F)cc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3n[nH]cc3NC(=O)c3cc(F)ccc3OC)[nH]c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of EDC (44 mg, 0.23 mmol) and HOBt (31 mg, 0.23 mmol) in DMF (5 ml) was added 3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.19 mmol) and 5-fluoro-2-methoxy-benzoic acid (36 mg, 0.21 mmol) and the mixture stirred at room temperature overnight. The solvent was removed in vacuo and the resulting solid partitioned between DCM (20 ml) and saturated aqueous sodium bicarbonate (20 ml). A precipitate was formed which was removed by filtration and oven dried to yield N-[3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-5-fluoro-2-methoxy-benzamide (64 mg, 81%). (LC/MS: Rt 2.64, [M+H]+ 412).
Reaction SMILES: [BH4-].[Na+].[C:3]([Si:7]([CH3:38])([CH3:37])[O:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[NH:23][C:24]([C:26]2[CH:27]=[N:28][N:29]3[CH:34]=[C:33]([CH:35]=[O:36])[CH:32]=[N:31][C:30]=23)=[O:25])[CH2:11][CH2:10]1)([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.O>[C:3]([Si:7]([CH3:38])([CH3:37])[O:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[NH:23][C:24]([C:26]2[CH:27]=[N:28][N:29]3[CH:34]=[C:33]([CH2:35][OH:36])[CH:32]=[N:31][C:30]=23)=[O:25])[CH2:11][CH2:10]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(Oc2ccc(Cl)cc2NC(=O)c2cnn3cc(C=O)cnc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCC(Oc2ccc(Cl)cc2NC(=O)c2cnn3cc(CO)cnc23)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium borohydride (30 mg, 0.079 mmol) was added to a solution of 6-formyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl}-amide (20 mg, 0.038 mmol) in a mixture of tetrahydrofuran (1.5 mL) and water (0.1 mL) and the resulting mixture was stirred at room temperature for 2.5 hours. The solvent was evaporated under reduced pressure to give 6-hydroxymethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl}-amide as an oily residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([NH:19][C@H:20]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=4)[CH2:21][CH2:22]OS(C)(=O)=O)=[O:18])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C=O)C>[N:38]([CH2:22][CH2:21][C@H:20]([NH:19][C:17]([C:16]1[C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]=2[CH:13]=[N:14][CH:15]=1)=[O:18])[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=1)=[N+:39]=[N-:40]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(S(C)(=O)=O)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc([C@H](CCN=[N+]=[N-])NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reaction time: 72 h

Procedure:
To a room temperature solution of methanesulfonic acid(S)-3-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-3-(2-methanesulfonyl-pyridin-4-yl)-propyl ester (122 mg, 0.223 mmol) in DMF (2 mL) was added sodium azide (19 mg, 0.29 mmol). After 72 hours, the reaction was quenched with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over magnesium sulfate, filtered and concentrated. The mixture was passed through a plug of silica gel eluting with a gradient of 0-5% methanol in dichloromethane to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid[(S)-3-azido-1-(2-methanesulfonyl-pyridin-4-yl)-propyl]-amide which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([CH3:11])[C:8](Cl)=[N:7][CH:6]=1)[CH3:2].C1C=CC(P([C:27]2[CH:32]=[CH:31]C=CC=2)C2C=CC=CC=2)=CC=1.[C:33]([O-])([O-])=O.[K+].[K+].N#N>COCCOC.CC(=O)OCC.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>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH:33]=[C:32]([CH3:31])[CH3:27])=[N:7][CH:6]=1)[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1cnc(Cl)c(C)c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(C=C(C)C)c(C)c1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
To a solution of 6-chloro-5-methyl-nicotinic acid ethyl ester (4.98 g, 24.9 mmol), 2,4,6-tri-(2-methyl-propenyl)-cycloboroxane pyridine complex (5.74 g, 17.7 mmol, prepared in analogy to a procedure given by F. Kerins, D. F. O'Shea J. Org. Chem. 67 (2002) 4968-4971), and PPh3 (1.15 g, 4.4 mmol) in DME (60 mL), a solution of 2 M aq. K2CO3 (20 mL) is added. The mixture is degassed and flushed with N2 before Pd(PPh3)4 (460 mg, 0.4 mmol) is added. The mixture is stirred at 90° C. for 20 h before it is cooled to rt, diluted with EA (150 mL) and washed with sat. aq. NaHCO3 (2×50 mL). The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by FC (SiO2, heptane-EA) to give 5-methyl-6-(2-methyl-propenyl)-nicotinic acid ethyl ester (3.98 g) as an orange oil; LC-MS: tR=0.72 min, [M+1]+=220.15.