Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][CH2:16][O:17][CH2:18][CH3:19]>CC[N+](CC1C=CC=CC=1)(CC)CC.[Cl-].C1(C)C=CC=CC=1.[OH-].[Na+]>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][O:14][CH2:19][CH2:18][O:17][CH:16]=[CH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1nccn1Cc1ccccc1
Reactant: CCOCC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=COCCOCc1nccn1Cc1ccccc1
Reaction time: 24 h
Yield: 85 %

Procedure:
0.54 g of TEBAC (2.4×10−3 mol) and 5.6 g of CEVE (0.05 mol) are added to a solution of 1-benzyl-2-hydroxymethylimidazole (4.7 g, 0.024 mol.) in toluene (15 ml). A basic solution 20 N in NaOH (100 ml) is then added in the medium and the heterogeneous mixture is brought to 90° C. for 24 h with vigorous stirring. After cooling, the solution is diluted with 250 ml of decanted ether, then the organic phase is washed with water until pH=7 (10×100 ml). The organic phase is dried on Na2SO4, filtered, then evaporated under reduced pressure to yield 5.3 g (85%) of desired product. Given the satisfactory purity of the obtained product, no further purification is required.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[N:14][C:15]([C:18]([O:20]CC)=O)=[C:16]([OH:17])[C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:23][CH2:24][C:25]([OH:27])=[O:26].[O-]CC.[Na+].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[N:14][C:15]([C:18]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:20])=[C:16]([OH:17])[C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ncc2c(-c3ccc(F)cc3)noc2c1O
Reactant: NCC(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1ncc2c(-c3ccc(F)cc3)noc2c1O
Temperature: 25 °C
Yield: 57.9 %

Procedure:
Ethyl 3-(4-fluorophenyl)-7-hydroxyisoxazolo[4,5-c]pyridine-6-carboxylate (0.11 g, 0.36 mmol) was dissolved in 10 mL of DMF. Glycine (0.55 g, 7.28 mmol) and sodium ethoxide (0.37 g, 5.46 mmol) were added and the mixture was refluxed for 14 h. The mixture was cooled to room temperature and diluted with 60 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 3. The resulting suspension was filtered and the solid was dried under vacuum to give 69 mg of the title compound. MS: (+) m/z 332.00 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[F:9].[Br:10]Br>[Fe]>[Br:10][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([F:9])[C:4]=1[CH3:8]
Reactant: Cc1cccc(F)c1F
Reactant: BrBr
Agent: [Fe]
Product: Cc1c(Br)ccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1,2-difluoro-3-methylbenzene (5 g, 39.0 mmol, commercially available from e.g. Sigma-Aldrich, Apollo or Fluorochem) containing iron (0.131 g, 2.342 mmol) was added bromine (2.011 ml, 39.0 mmol) dropwise maintaining a temperature of <30° C. with ice cooling. The mixture was stirred at room temperature overnight. The mixture was partitioned between water (50 mL) and diethyl ether (100 mL). The aqueous phase was extracted with diethyl ether (3×50 mL), combined organic extracts were washed with water (50 mL), 5% sodium thiosulfate solution (50 mL), water (50 mL), brine (50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to afford product in 8.07 g. (Caution: by of product=68-70° C. @ 57 mBar).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:22]1[C:23]([O:29][CH3:30])=[N:24][CH:25]=[C:26]([Br:28])[CH:27]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.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]>[Br:28][C:26]1[CH:27]=[C:22]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)[C:23]([O:29][CH3:30])=[N:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: COc1ncc(Br)cc1Br
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ncc(Br)cc1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 110 °C
Reaction time: 12 h
Yield: 34.5 %

Procedure:
(R)-tert-Butyl 3-aminopiperidine-1-carboxylate (2.99 g, 15.0 mmol) and cesium carbonate (9.84 g, 30.0 mmol) were added to a solution of 3,5-dibromo-2-methoxypyridine (4.00 g, 15.0 mmol) in dioxane (100 mL). The mixture was degassed for 20 min and then Xphos (0.692 g, 1.20 mmol) and Pd2(dba)3 (1.10 g, 1.20 mmol) were added. The mixture was stirred at 110° C. for 12 h. The mixture was allowed to cool to room temperature and was filtered through celite and concentrated. The residue was purified by chromatography using 5-10% ethyl acetate in pet ether to give 2 g of the desired compound: 1H NMR (300 MHz, DMSO-d6) 7.44 (narrow m, 1H), 6.95 (s, 1H), 5.15-5.20 (m, 1H), 3.91 (s, 3H), 3.50-3.95 (m, 2H), 3.20-3.40 (m, 1H), 2.80-3.05 (m, 2H), 1.80-1.95 (m, 1H), 1.10-1.70 (m, 3H), 1.36 (s, 9H); MS (ES) m/z 386, 384 (M+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:16]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1>>[NH:25]1[C:21]([C:17]2[CH:16]=[C:15]([NH:14][S:10]([C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[CH:3]=3)(=[O:12])=[O:11])[CH:20]=[CH:19][CH:18]=2)=[N:22][N:23]=[N:24]1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1cc2ccccc2s1
Yield: 60 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with 1-benzothiophene-2-sulfonyl chloride (12.8 mg, 0.055 mmol) and 5-(3-amino-phenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 60% yield (10.8 mg). MS (ESI+) calcd mass for C15H11N5O2S2 357.035416, found 357.036256.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]1)(C(C)(C)C)(C)C.Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[N:23]=1>CC(O)C>[Br:24][C:22]1[N:23]=[C:18]([NH:16][C:14]2[CH:13]=[N:12][N:11]([CH2:10][CH2:9][OH:8])[CH:15]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)OCCn1cc(N)cn1
Reactant: Cn1cc(Br)nc(Br)c1=O
Solvent: CC(C)O
Product: Cn1cc(Br)nc(Nc2cnn(CCO)c2)c1=O
Temperature: 90 °C
Yield: 115.1 %

Procedure:
A flask equipped with a magnetic stirrer was charged with 1-(2-(tert-butyldimethylsilyloxy)ethyl)-1H-pyrazol-4-amine 116b (1.7 g, 7.1 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (1.25 g, 4.7 mmol), and IPA (25 mL). The system was evacuated and then refilled with N2. The reaction mixture was heated at 90° C. for 6 h. Then, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate to afford 140a (1.7 g, 78%). LCMS: [M+H]+ 314.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14]1.O>C(Cl)Cl>[CH:12]([CH:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14]1)=[O:11]
Reactant: O=C(OCc1ccccc1)N1CCC(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: O=CC1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
DMSO (597 μL, 8.42 mmol) was added to a solution of oxalyl chloride (427 μL, 5.05 mmol) in DCM (25 mL) at −78° C. After 5 minutes, benzyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (generated in Step 1) was added. The reaction was continued for 30 minutes at −78° C. TEA (2.3 mL, 17 mmol) was then added. The resulting mixture was then allowed to warm to room temperature over the course of 30 minutes. Water was then added. The layers were separated and the organic phase was washed sequentially with 0.1 N HCl, water, saturated NaHCO3, and brine. The organic phase was then dried over sodium sulfate and the solvent was removed in vacuo to afford the product (0.82 g, 88% over two steps).
Reaction SMILES: NCC(O)=O.COC1C=C(OC)C=CC=1C=O.[OH-].[Na+].Cl.[CH3:21][O:22][C:23]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:24]=1[CH2:25][NH:26][CH2:27][C:28]([OH:30])=[O:29].[Cl-].[Na+].[C:39]12[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=1)[NH:44][C:43](=[O:50])[O:42][C:40]2=O>CO.CS(C)=O.[Pd].O>[CH3:21][O:22][C:23]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:24]=1[CH2:25][NH:26][CH2:27][C:28]([OH:30])=[O:29].[CH3:21][O:22][C:23]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:24]=1[CH2:25][N:26]1[C:40](=[O:42])[C:39]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[NH:44][C:43](=[O:50])[CH2:27]1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [Pd]
Agent: COc1ccc(C=O)c(OC)c1
Agent: COc1ccc(CNCC(=O)O)c(OC)c1
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN2CC(=O)Nc3ccccc3C2=O)c(OC)c1
Reaction time: 0.5 h

Procedure:
N-(2,4-dimethoxybenzyl)glycine is prepared by the reaction of glycine with 2,4-dimethoxybenzaldehyde in the presence of sodium hydroxide, reduction with palladium-on-carbon in methanol and subsequent neutralisation with 2 N hydrochloric acid. The aqueous solution obtained is concentrated. 41.9 g of this mixture of N-(2,4-dimethoxybenzyl)-glycine and sodium chloride are stirred at 110° C. for 1.5 hours in 300 ml of dimethyl sulphoxide with 23.18 g (142 mmol) of isatoic acid anhydride. The mixture is poured into ca 2 liters of water and stirred for 0.5 hour. The separated crystals are filtered off under suction, washed with water and dried. After recrystallisation from ethyl acetate, there is obtained 3,4-dihydro-4-(2,4-dimethoxybenzyl)-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 151°-152.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[CH:19][C:18]4=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[C:26]([CH:30]=O)[CH:27]=[N:28][CH:29]=5)[N:17]4[N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:32][S:33]([CH2:36][CH2:37][NH2:38])(=[O:35])=[O:34].Cl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:32][S:33]([CH2:36][CH2:37][NH:38][CH2:30][C:26]1[CH:25]=[C:24]([C:23]2[N:17]3[C:18]([CH:19]=[N:20][C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[CH:13][CH:12]=4)=[N:16]3)=[CH:21][CH:22]=2)[CH:29]=[N:28][CH:27]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)CCN
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cncc(C=O)c5)n4n3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cncc(CNCCS(C)(=O)=O)c5)n4n3)cc2)CC1
Temperature: 45 °C
Reaction time: 3 h
Yield: 6 %

Procedure:
Into a 8-dram vial, 5-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-pyridine-3-carbaldehyde (100.2 mg, 0.2424 mmol), 2-Methanesulfonyl-ethylamine; hydrochloride (0.2322 g, 1.454 mmol), 1,2-Dichloroethane (15.0 mL), and Acetic acid (100.0 uL, 1.759 mmol) were added and heated at 45° C. overnight. Sodium triacetoxyborohydride (0.1541 g, 0.7273 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction was partitioned with saturated NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (5 to 25% methanol). The collected fractions afforded (7-{5-[(2-Methanesulfonyl-ethylamino)-methyl]-pyridin-3-yl}-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine as a yellow solid (8 mg, 6%). LCMS (E/I+) 521.19 (M+H). NMR 1H (DMSO-d6)-9.27 (s, 1H), 9.19 (d, 1H, J=2.25 Hz), 8.97 (s, 1H), 8.57 (t, 1H, J=1.90 Hz), 8.52 (d, 1H, J=1.61 Hz), 7.56 (d, 2H, J=8.79 Hz), 7.27 (d, 1H, J=5.28 Hz), 6.95 (d, 1H, J=5.28 Hz), 6.92 (d, 1H, J=8.79 Hz), 3.84 (d, 2H, J=5.80 Hz), 3.25 (t, 2H, J=6.63 Hz), 3.08 (t, 4H, J=4.97 Hz), 3.00 (s, 3H), 2.94 (q, 2H, J=6.63 Hz), 2.46 (t, 4H, J=4.97 Hz), 2.24 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]1[N:16]=[CH:17][N:18]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:19]=1)[N:7]=[C:6]2[CH2:39]O.S(Cl)([Cl:43])=O.C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>ClCCl.C(O)C>[Cl:43][CH2:39][C:6]1[C:5]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([CH2:14][C:15]2[N:16]=[CH:17][N:18]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:19]=2)[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(CO)nn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Product: COc1cc2c(CCl)nn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2cc1OC

Procedure:
In 1700 ml of dichloromethane was suspended 180.0 g of 5,6-dimethoxy-1-(1-trityl-4-imidazolyl)methyl-1H-indazole-3-methanol, having been ground to powder in a mortar, at room temperature, followed by stirring while cooling with ice. To the reaction mixture was added dropwise 48.6 ml of thionyl chloride over 5 minutes. One minute later, the spot of the starting material on a thin layer chromatogram (chloroform:ethanol=30:1) disappeared. The reaction mixture was poured into 2000 ml of a saturated sodium hydrogencarbonate aqueous solution and extracted with 5000 ml of chloroform. The extract was dried over sodium sulfate, filtered, and the solvent was evaporated to yield 165.1 g of a colorless solid. This solid was used in the subsequent reaction without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:7]=1[CH2:8][OH:9].C(N(CC)CC)C>C(Cl)Cl.O>[F:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:7]=1[CH2:8][O:9][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: OCc1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCc1c(F)cccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
Acetyl chloride (1.13 mL, 15.8 mmol) was added dropwise to a solution of 2,6-difluorobenzyl alcohol (1.76 g, 12.2 mmol) and triethylamine (3.43 mL, 24.4 mmol) in DCM (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with water and extracted with DCM (3×20 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a colourless oil (1.72 g, 76%). 1H NMR 400 MHz δ (CDCl3): 7.37-7.28 (1H, m), 6.96-6.88 (2H, m), 5.20 (2H, s), 2.08 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9](I)=[CH:10][C:3]=12.[CH:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22].C(=O)(O)[O-].[Na+]>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.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:21]=[O:22])[CH:28]=3)=[CH:10][C:3]=12
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: O=S(=O)(c1ccccc1)n1c(I)cc2c(Br)ccnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(-c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
In a sealed pressure tube was added 4-bromo-2-iodo-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine (2.1 mmol; preparation disclosed in WO03/000690A1), 3-formylbenzeneboronic acid (2.1 mmol), N,N-dimethylformamide (15 mL), aqueous saturated sodium bicarbonate (5 mL) and tetrakis(triphenylphosphine)palladium(0) (0.1 mmol). The reaction was purged with nitrogen, capped and stirred at 100° C. for 16 h. After cooling to room temperature the reaction was concentrated under vacuum, taken up in ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and evaporated to dryness under vacuum. Purification by flash chromatography by silica gel (0-4% ethyl acetate in methylene chloride) gave the title compound as a white solid (77%). ESMS [M+H]+: 441.2
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][O:14][C@@H:15]1[C@@H:21]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[O:20][C@H:17]([O:18][CH3:19])[C:16]1=[O:33].O>CCOCC>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][O:14][C@@H:15]1[C@@H:21]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[O:20][C@H:17]([O:18][CH3:19])[C@:16]1([CH2:2][CH3:1])[OH:33]
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)C1=O
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: O
Product: CC[C@]1(O)[C@@H](OC)O[C@H](COCc2ccc(Cl)cc2Cl)[C@H]1OCc1ccc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To diethyl ether (300 mL) at −78° C. was slowly added EtMgBr (3.0 M, 16.6 mL) and then dropwise the compound from Step B of Example 62 (4.80 g, 10.0 mmol) in anhydrous Et2O (100 mL). The reaction mixture was stirred at −78° C. for 15 min, allowed to warm to −15° C. and stirred for another 2 h, and then poured into a stirred mixture of water (300 mL) and Et2O (600 mL). The organic phase was separated, dried (MgSO4), and evaporated in vacuo. The crude product was purified on silica gel using ethyl acetate/hexane (1:2) as eluent. Fractions containing the product were pooled and evaporated in vacuo to give the desired product (3.87 g) as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].[C:31]([C:35]1[N:39]2[N:40]=[C:41](Cl)[CH:42]=[CH:43][C:38]2=[N:37][N:36]=1)([CH3:34])([CH3:33])[CH3:32]>O1CCCC1>[C:31]([C:35]1[N:39]2[N:40]=[C:41]([O:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)[CH:42]=[CH:43][C:38]2=[N:37][N:36]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CC(C)(C)c1nnc2ccc(Cl)nn12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1nnc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Temperature: 60 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
991 mg of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 20 ml of tetrahydrofuran; 322 mg of sodium tert-butoxide was added, followed by stirring at an external temperature of 60° C. for 2 hours. After cooling, 642 mg of 3-tert-butyl-6-chloro[1,2,4]triazolo[4,3-b]pyridazine was added, followed by refluxing under heating for 2 hours. After cooling, saline was added; the reaction mixture was extracted with ethyl acetate and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; 1.26 g of the residue was dissolved in 3 ml of pyridine; 1.5 ml of acetic anhydride was added, followed by stirring at room temperature for 6 hours. After the reaction mixture was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; the residue crystallized from ethyl acetate-diethyl ether (1:1), washed with diethyl ether, and dried, to yield 500 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][C:10]=2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[CH2:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:19][C:20]3[CH2:28][C:27]4[C:22]([CH:21]=3)=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: ClCC1=Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc2c(s1)CCN(CC1=Cc3ccccc3C1)CC2
Yield: 4 %

Procedure:
Prepared from 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine, potassium carbonate and 2-chloromethyl-1H-indene (prepared from 1H-indene, paraformaldehyde and concentrated hydrochloric acid) in anhydrous dimethylformamide for 2 hours at 50° C. Yield: 4% of theory, Melting point: 134°-138° C.
Reaction SMILES: FC(F)(F)[C:3]([C:5]1[N:6]=[C:7]([CH2:14][CH2:15][CH3:16])[N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4].[OH-:19].[K+]>CCO>[CH2:14]([C:7]1[N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[C:5]([C:3]([OH:4])=[O:19])[N:6]=1)[CH2:15][CH3:16]
Reactant: CCCc1nc(C(=O)C(F)(F)F)c2ccccn12
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: CCCc1nc(C(=O)O)c2ccccn12
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.2 %

Procedure:
To a solution of 2,2,2-trifluoro-1-(3-propyl-imidazo[1,5-a]pyridin-1-yl)-ethanone (379 mg, 1.48 mmol) in EtOH (10 mL) was added KOH (830 mg, 14.8 mmol). The mixture was stirred at ambient temperature for 15 h. After this time the mixture was concentrated, diluted with water (10 mL) and acidified to pH 3 with 2N HCl. The aqueous mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to yield the title compound (170 mg, 56%). 1H NMR (DMSO-d6) δ 12.1 (1H), 8.38 (1H), 7.99 (1H), 7.18 (1H), 6.90 (1H), 2.99 (2H), 1.79 (2H), 0.98 (3H); m/z (M+H)=205.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][C:6](C(O)=O)=[CH:5]2.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:29])C=CC=CC=1.Cl>ClCCl.C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][C:6](=[O:29])[CH2:5]2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C1=Cc2cc(Cl)ccc2OC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1COc2ccc(Cl)cc2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-chloro-2H-chromene-3-carboxylic acid (Avocado, 4.90 g, 23.3 mmol) in dichloromethane (50 mL) was added triethylamine (4 mL) and diphenylphosphoryl azide (7.04 g, 25.6 mmol) in toluene (20 mL). The flask was equipped with a Dean-Stark trap, and the mixture was heated to reflux. After 1.5 hours, toluene (50 mL) was added and the mixture continued to reflux for 2.5 hours and was then cooled to ambient temperature. Hydrochloric acid (6N, 40 mL) was added, and the biphasic mixture was heated at reflux for 3.5 hours then cooled to ambient temperature. Ethyl acetate (200 mL) and water (200 mL) were added and the separated organic layer was washed sequentially with saturated sodium bicarbonate (2×200 mL) followed by brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrate under reduced pressure, and chromatographed on silica gel eluting with 10-to-60% dichloromethane in hexane to afford the title compound. MS (DCI) m/z 181.97 (M+H)+.