Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25](I)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH:29]([C:31]1[O:32][C:33](B(O)O)=[CH:34][CH:35]=1)=[O:30].COCCOC.CO>[Pd].C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:33]3[O:32][C:31]([CH:29]=[O:30])=[CH:35][CH:34]=3)[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4ccc(I)cc34)cc2Cl)c1
Agent: [Pd]
Solvent: CO
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Temperature: 50 °C

Procedure:
To a reaction vessel was added N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodo-4-quinazolinamine (100 mg; 0.198 mmol), 2-formylfuran-5-boronic acid (Frontier Scientific, 42 mg; 0.297 mmol), 10% palladium on activated carbon (5 mg; 0.05 wt), DME (2.0 mL), MeOH (1.0 mL) and triethylamine (83 μL). After heating at 50° C. for 14 h, a HPLC indicated 98.5% clean conversion. 1H NMR (d6-DMSO) δ: 11.44 (s, 1H), 9.38 (s, 2H), 9.11 (s, 1H), 8.90 (s, 1H), 8.39 (dd, 1H, J=8 and 4 Hz), 7.89 (d, 1H, J=12 Hz), 7.84 (d, 1H, J=4 Hz), 7.60 (dd, 1H, J=8 and 4 Hz), 7.47–7.42 (m, 2H), 7.44 (AA′BB′, 2H, JAB=8 Hz), 7.35–7.25 (m, 3H), 7.24 (d, 1H, J=4 Hz), 7.16 (dt, 1H, J=8 and 4 Hz), 7.06 (AA′BB′, 2H, JAB=8 Hz, 6.84 (d, 1H, J=4 Hz), 5.27 (s, 2H), 4.43 (s, 2H), 3.61–3.50 (m, 2H), 3.47–3.36 (m, 2H), 3.09 (s, 3H), 2.23 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:26](COCC[Si](C)(C)C)[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[N:20]=[C:15]2[CH:14]=1.C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:26][C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[N:20]=[C:15]2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CNC(C)=O)cnc3n1COCC[Si](C)(C)C)cn2C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: NCCN
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3nc(CNC(C)=O)cnc3[nH]1)cn2C
Temperature: 85 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
N-((6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)acetamide (0.200 g, 0.417 mmol) in DMF (10 mL) was treated with ethylenediamine (0.90 mL, 13 mmol) and TBAF (1 M in THF, 1.7 mL, 1.7 mmol). The mixture was heated to about 85° C. for about 90 min then cooled and concentrated under reduced pressure. The material was stirred with water (20 mL) for about 16 h, Et2O (10 mL) was added, and stirring was continued for about 15 min. The slurry was filtered and the solid collected was dried. The filtrate was extracted with EtOAc (2×25 mL) then the combined organic solutions were dried over anhydrous MgSO4, filtered, and concentrated to give material, which was combined with the previously collected solid. The material was triturated with EtOAc (5 mL) and filtered to give a solid. The filtrate was purified by silica gel chromatography eluting with DCM/MeOH (9:1) to give an additional amount of product which was combined with the solid obtained from the EtOAc trituration to give N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)acetamide (0.108 g, 74%): LC/MS (Table 2, Method a) Rt=1.91 min; MS m/z: 350.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH3:13])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:25]([O-])=O)[CH:21]=2)[N:16]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH3:13])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH2:25])[CH:21]=2)[N:16]=1
Reactant: COc1c(Cl)cc(Cl)c2c1C(Nc1ccc3cc([N+](=O)[O-])ccc3n1)CC2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1c(Cl)cc(Cl)c2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Temperature: 25 °C

Procedure:
Rac-(4,6-dichloro-7-methoxy-indan-1-yl)-(6-nitro-quinolin-2-yl)-amine (250 mg, 0.62 mmol) were taken up in a mixture of ethanol (5 mL) and water (2.5 mL). After the addition of ammonium chloride (17 mg, 0.31 mmol) and iron powder (173 mg, 3.1 mmol) the reaction mixture was heated tom reflux for 6 h. After cooling to ambient temperature the reaction mixture was filtered through Dicalit®, the filtrate was concentrated and the residue was subjected to column chromatography (silica gel, heptane ethyl acetate gradient 9:1→1:1). Rac-N2-(4,6-dichloro-7-methoxy-indan-1-yl)-quinoline-2,6-diamine was obtained as a yellow oil (0.11 g, 45%); MS: m/e=375.4 (M+H+).
Reaction SMILES: [CH3:1][C:2](=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:23](O)[CH2:24][OH:25].C1C=CC=CC=1>O>[CH2:24]1[O:25][C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9])([CH3:1])[O:10][CH2:23]1
Reactant: OCCO
Reactant: C=CCCCCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C=CCCCCCC1(C)OCCO1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
A solution containing 119.0 g of non-8-en-2-one, (prepared in Example 22 B-3), 1.2 g p-toluenesulfonic acid monohydrate, 63.1 g of ethylene glycol and 420 ml anhydrous benzene was prepared and refluxed for about 15 to 17 hr. Water which formed was collected in a Dean-Stark trap. The solution was cooled to room temperature and 250 ml of 5% aqueous sodium bicarbonate solution was added thereto. The benzene layer was separated and dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was distilled to yield 116.8 g of title compound having the following physical characteristics:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16].[CH2:24]([N+:26](CC)(CC)CC)C>O1CCOCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Cu].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:24]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH3:13])[C:4](=[O:14])[C:3]([C:15]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16])=[C:2]2[OH:1])#[N:26]
Reactant: CCOC(=O)CNC(=O)c1c(O)c2cc(I)ccc2n(C)c1=O
Reactant: CC[N+](CC)(CC)CC
Agent: [Cu]
Agent: [Fe+2]
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOC(=O)CNC(=O)c1c(O)c2cc(C#N)ccc2n(C)c1=O
Temperature: 145 °C
Yield: 90 %

Procedure:
Ethyl 2-(4-hydroxy-6-iodo-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.200 g, 0.46 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.048 g, 0.087 mmol), Copper cyamide (0.194 g, 2.2 mmol) and Tris(dibenzylideneacetone)dipalladium (0.020 g, 0.022 mmol) in 1,4-dioxane (2 ml) were combined in a 10 ml tube. Tetraethylammonium cyamide (0.085 g, 0.54 mmol) and 1,4-dioxane (1 ml) were added and the tube was sealed and heated to 145° C. for 15 min under Argon in a microwave (Personal Chemistry 300 W). After cooling, the mixture was filtered and washed with methylene chloride (50 ml). The filtrate was washed with deionized water (3×50 ml), then with brine (50 ml), dried over magnesium sulfate then concentrated and dried in vacuo. Flash column chromatography (Silica gel, 0-100% methylene chloride in hexane) gave a solid which washed with diethyl ether, filtered and dried in vacuo to give ethyl 2-(6-cyano-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.135 g, 90% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:28][C:27]3[CH:29]=[CH:30][C:24]([C:21](=[O:23])[CH3:22])=[CH:25][CH:26]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: CC(=O)c1ccc(N)cc1
Product: CC(=O)c1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Yield: 39.4 %

Procedure:
A procedure similar to that described in Example 51 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and p-acetylaniline (80 mg, 0.59 retool) to give 90 mg of the title compound (38%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.07 (s, 1H), 10.35 (s, 1H), 7.93 (d, 2H, J=9 Hz), 7.70 (d, 1H, J=9 Hz), 7.24 (d, 1H, J=2 Hz), 7.17 (d, 2H, J=9 Hz), 5.17~5.27 (m, 1H), 3.05 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=16.8 Hz), 2.65 (d, 2H, J=6.9 Hz), 2.53 (s, 3H), 2.12 (dm, 1H, J=13.5 Hz), 1.80~1.97 (m, 1H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:9]=1[C@H:16]1[NH:20][C@@H:19]([C:21](OCC)=[O:22])[CH2:18][CH2:17]1.O.[OH-].[Na+]>C1COCC1>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:9]=1[C@H:16]1[NH:20][C@@H:19]([CH2:21][OH:22])[CH2:18][CH2:17]1
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2c(F)cc(F)cc2F)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC[C@H]1CC[C@@H](c2c(F)cc(F)cc2F)N1
Temperature: -15 °C
Reaction time: 19 h
Yield: 100.2 %

Procedure:
LAH (724 mg) was added to a solution of ethyl (2R,5S)-5-(2,4,6-trifluorophenyl)pyrrolidine-2-carboxylate (4.34 g) in THF (100 mL) at −15° C. over one hour. The reaction solution was stirred at −15° C. for 19 hours. Water (0.8 mL), a 5 N sodium hydroxide solution (0.8 mL), and water (2.5 mL) were sequentially added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 3.68 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH2:22])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH:22][C:29](=[O:30])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Reactant: O=C(O)c1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12)c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To a mixture of (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Example 6, Step A; 30 mg, 0.1 mmol), picolinic acid (15 mg, 0.12 mmol), and HATU (46 mg, 0.12 mmol) was added 0.7 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.053 mL, 0.3 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 10 minutes. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 70% acetonitrile/water to yield the final product as a yellowish solid (35 mg, 86% yield). MS (apci) m/z=403.2 (M+H).
Reaction SMILES: [Br-:1].[C:2]([CH:5]([CH2:18][CH3:19])[CH2:6][CH2:7][N+:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]=1[CH3:17])([OH:4])=[O:3].C(O[C:24](=O)[CH3:25])(=O)C>C(O)(=O)C>[Br-:1].[NH:8]([CH:7]=[CH:24][CH:25]=[CH:17][C:9]1[S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:8]=1[CH2:7][CH2:6][CH:5]([C:2]([OH:4])=[O:3])[CH2:18][CH3:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:11]=1
Reactant: CCC(CC[n+]1c(C)sc2ccccc21)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: [Br-]
Solvent: CC(=O)O
Product: CCC(CC[n+]1c(C=CC=CNc2ccccc2)sc2ccccc21)C(=O)O

Procedure:
The desired compound is prepared by heating 344 g of 3-carboxypentyl-2-methylbenzothiazolium bromide, 5.14 g of malonaldehyde dianil hydrochloride and 2 mL of acetic anhydride in 30 mL of acetic acid for 6 hours.
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=O)[CH2:3][NH:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]1[CH:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[CH2:4][CH2:3][NH:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: O=C1CNCC2c3ccccc3CCN12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)CCN1CCNCC21
Temperature: 0 °C
Yield: 98.1 %

Procedure:
1,2,3,6,7,11b-Hexahydro-pyrazino[2,1-a]isoquinolin-4-one (3.03 g, 15.0 mmol) was added to a solution of lithium aluminum hydride (1.14 g, 30.0 mmol) in tetrahydrofuran (63 ml) and the mixture was refluxed for 6 hours. Water (1.2 ml), 15% aqueous sodium hydroxide (1.2 ml) and water (3.2 ml) were added sequentially to the ice-cooled solution, and filtration of the precipitate and removal of the solvent under reduced pressure afforded 1,3,4,6,7,11b-hexahydro-2H-pyrazino[2,1-a]isoquinoline (2.77 g, 98%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[CH:23]=[O:24].COC1C=C(C(C2C=CC=C(OC)C=2)=CC#N)C=C(OC)C=1>>[CH3:29][O:28][C:26]1[CH:25]=[C:22]([CH:23]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=2)[OH:24])[CH:21]=[C:20]([O:19][CH3:18])[CH:27]=1
Reactant: CCOc1cc(Br)ccc1OC
Reactant: COc1cc(C=O)cc(OC)c1
Agent: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Agent: [Li]CCCC
Product: CCOc1cc(C(O)c2cc(OC)cc(OC)c2)ccc1OC
Yield: 79.7 %

Procedure:
4-bromo-2-ethoxy-1-methoxybenzene (0.66 g, 2.86 mmol), n-butyl lithium (1.14 ml, 2.86 mmol), and 3,5-dimethoxybenzaldehyde (0.43 g, 2.60 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude was purified via flash column chromatography (20% EtOAc in hexane gradient to 50% EtOAc in hexane in about 40 min.) to give (3,5-dimethoxy-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanol as an off-white solid (0.66 g, 80%): 1HNMR (CDCl3) δ 6.92-6.80 (m, 3H, Ar), 6.54 (d, J=2 Hz, 2H, Ar), 6.36 (t, J=2 Hz, 1H, Ar), 5.70 (d, J=3 Hz, 1H, CHOH), 4.07 (q, J=6 Hz, 2H, CH2CH3), 3.85 (s, 3H, OCH3), 3.76 (s, 6H, 2OCH3), 2.19 (d, J=3 Hz, 1H, OH), 1.44 (t, J=7 Hz, 3H, CH2CH3). The product was carried over to the next step.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([CH3:12])=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:8][C:7]=2[C:6]([O:18][CH3:19])=[CH:5][CH:4]=1)=[O:2].S(=O)(=O)([OH:22])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[CH2:16]([O:15][C:13]([C:9]1[O:8][C:7]2[C:6]([O:18][CH3:19])=[CH:5][CH:4]=[C:3]([C:1]([OH:22])=[O:2])[C:11]=2[C:10]=1[CH3:12])=[O:14])[CH3:17]
Reactant: CCOC(=O)c1oc2c(OC)ccc(C=O)c2c1C
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1oc2c(OC)ccc(C(=O)O)c2c1C

Procedure:
The solution of ethyl 4-formyl-7-methoxy-3-methylbenzo[b]furan-2-carboxylate (3.0 g, 11.4 mmol) in acetone (30 ml) was cooled to 10-20° C. Sulfamic acid (1.55 g, 17.1 mmol) was added at once to the reaction mixture at 10-20° C. Then solution of sodium chlorite (1.6 g, 17.1 mmol) in water (10 ml) was added dropwise at the same temp. Water (100 ml) was added to reaction mixture. Acetone was distilled off under vacuum. The solid obtained was filtered and suck dried. Yellow coloured solid (3.0 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1>O.C(O)C>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)=[N:5][N:6]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Nc1nnc(S)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nnc(SCc2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.2 %

Procedure:
In 35 ml of water and 70 ml of ethanol, 12.8 g of 2-amino-5-mercapto-1,3,4-thiadiazol and 43 g of sodium hydroxide were added. To this mixture, 14.8 g of 4-chlorobenzyl chloride was added and the mixture was stirred at room temperature for 1 hour. Water was added and the reaction mixture was filtered. The residue was washed with water and an ethanol/n-hexane (1:1) mixture, and was dried under reduced pressure, and thus 23:1 g of 2-amino-5-(4-chlorobenzylthio)-1,3,4-thiadiazole was obtained.
Reaction SMILES: [CH:1]([S:5][C:6]1[S:7][CH:8]=[C:9]([O:11][S:12]([CH3:15])(=[O:14])=[O:13])[N:10]=1)([CH2:3][CH3:4])[CH3:2].[OH:16]O.O.[OH-].[Na+]>C(O)(=O)C>[CH:1]([S:5]([C:6]1[S:7][CH:8]=[C:9]([O:11][S:12]([CH3:15])(=[O:13])=[O:14])[N:10]=1)=[O:16])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)Sc1nc(OS(C)(=O)=O)cs1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCC(C)S(=O)c1nc(OS(C)(=O)=O)cs1
Yield: 49.7 %

Procedure:
4.0 g of 2-sec-butylthio-4-methylsulfonyloxy-1,3-thiazole was dissolved in 15 ml of acetic acid, and 2.2 ml of 35% aqueous hydrogen peroxide was added to the solution at room temperature, followed by reaction at 30° to 40° C. for 4 hours. The reaction mixture was poured into chilled water, neutralized by 5% aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of common salt, dried over anhydrous sodium sulfate and concentrated to obtain an oil, which was purified by silica-gel column chromatography to 2.1 g of the objective compound as a pale yellow oil (yield: 49.7%).
Reaction SMILES: C(N)(C)(C)C.[Br:6]Br.[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17].O>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:19][O:18][C:16](=[O:17])[CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([Br:6])[C:9]=1[OH:8]
Reactant: COC(=O)Cc1ccccc1O
Reactant: BrBr
Solvent: O
Solvent: CC(C)(C)N
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cccc(Br)c1O
Temperature: -30 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butylamine (1.74 mL, 16.4 mmol, 1.50 eq.) in toluene (54 mL), bromine (0.47 mL, 9.2 mmol, 0.84 eq.) was added dropwise at −30° C. The mixture was stirred at −30° C. for 1 hour then cooled down to −78° C. and a solution of methyl 2-(2-hydroxyphenyl)acetate (1.82 g, 11.0 mmol, 1.00 eq.) in DCM (10 mL) was slowly added. The resulting mixture was stirred at r.t. for 18 hours. Water was added and the layers were separated. The aq. phase was extracted with DCM (2×). The comb. org. layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give (3-bromo-2-hydroxy-phenyl)-acetic acid methyl ester as a pale yellow oil that solidified upon standing.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH:12]=2)=[CH:4][C:3]=1[C:17]1[NH:21][C:20]2[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:19]=2[N:18]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:32][NH2:33].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O.C(OCC)(=O)C.C(Cl)CCl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][C:14]([NH:33][CH2:32][C:31]3[CH:34]=[CH:35][C:36]([F:37])=[C:29]([F:28])[CH:30]=3)=[O:16])[CH:12]=2)=[CH:4][C:3]=1[C:17]1[NH:21][C:20]2[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:19]=2[N:18]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: COc1ccc2nc(-c3cc(-c4cnn(CC(=O)O)c4)cnc3N)[nH]c2c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: COc1ccc2nc(-c3cc(-c4cnn(CC(=O)NCc5ccc(F)c(F)c5)c4)cnc3N)[nH]c2c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4a.2 146 mg of {4-[6-amino-5-(6-methoxy-1H-benzimidazol-2-yl)pyridin-3-yl]pyrazol-1-yl}acetic acid (0.120 mmol) are dissolved in 1.5 ml of DMF. 17.5 mg (0.120 mmol) of 3,4-difluorobenzylamine, 16.2 mg (0.120 mmol) of HOBt, 23 mg (0120 mmol) of EDC and 26.4 μl (0.240 mmol) of N-methylmorpholine are added. The reaction mixture is stirred at room temperature for 14 h, and water/ethyl acetate is subsequently added. The aqueous phase is extracted 2× with ethyl acetate. The combined organic phases are washed with water, dried using sodium sulfate, filtered and evaporated to dryness. The residue is purified by means of preparative RP-HPLC, giving 2-{4-[6-amino-5-(6-methoxy-1H-benzimidazol-2-yl)pyridin-3-yl]pyrazol-1-yl}-N-(3,4-difluorobenzyl)acetamide; HPLC-MS [M+H]+ 490.2;
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[C:10](=O)([O-])[O-].[K+].[K+].CI>C1COCC1.CN(C=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)o1
Reaction time: 18 h
Yield: 100.2 %

Procedure:
To a stirred solution of 25.0 g (198 mmol) 5-methyl-2-furoic acid in 160 ml THF and 100 ml DMF were added 110 g (793 mmol) potassium carbonate and 49 ml (787 mmol) methyl iodide and stirring continued for 18 hours at room temperature. The reaction mixture was then filtered and the filtrate concentrated in vacuo. The residue was then partitioned between ether and water, the phases separated, and the aqueous phase further extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Chromatography (hexane then ethyl acetate/hexane 1/9) afforded 27.8 g (100%) methyl 5-methyl-2-furoate as a yellow oil. EI-MS m/e (%): 140 (M+, 44), 109 ([M—OMe]+, 100).
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[N:4]([CH2:12][CH3:13])[N:3]=1.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15].C(N(CC)CC)C>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:12]([N:4]1[C:5]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:6][C:2]([C:15]#[C:14][Si:16]([CH3:19])([CH3:18])[CH3:17])=[N:3]1)[CH3:13]
Reactant: CCn1nc(Br)nc1N1CCCC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCn1nc(C#C[Si](C)(C)C)nc1N1CCCC1
Temperature: 120 °C
Yield: 47.5 %

Procedure:
A mixture of 3-bromo-1-ethyl-5-(pyrrolidin-1-yl)-1H-1,2,4-triazole (240 mg, 979 μmol, Eq: 1.00), ethynyltrimethylsilane (192 mg, 275 μl, 1.96 mmol, Eq: 2) and triethylamine (149 mg, 205 μl, 1.47 mmol, Eq: 1.5) in tetrahydrofuran (3.65 ml) was purged for 5 minutes with nitrogen. Then copper (I) iodide (1.86 mg, 9.79 μmol, Eq: 0.01), bis(triphenylphosphine)palladium(II) chloride (6.87 mg, 9.79 μmol, Eq: 0.01) and triphenylphosphine (2.57 mg, 9.79 μmol, Eq: 0.01) were added, the vessel was capped and heated to 120° C. for 1 day. Once more copper (I) iodide (1.86 mg, 9.79 μmol, Eq: 0.01), triphenylphosphine (2.57 mg, 9.79 μmol, Eq: 0.01), bis(triphenylphosphine)palladium(II) chloride (6.87 mg, 9.79 μmol, Eq: 0.01) and ethynyltrimethylsilane (192 mg, 275 μl, 1.96 mmol, Eq: 2) were added, the vial was purged with argon, capped again and stirred for one more day at 120° C. The crude material was applied on silica gel and purified by flash chromatography over a 20 g silica gel column using heptane/ethyl acetate 10-30% as eluent affording 1-ethyl-5-pyrrolidin-1-yl-3-trimethylsilanylethynyl-1H-[1,2,4]triazole (122 mg, 47.5%) as an orange oil. MS: m/z=263.4 (M+H+)