Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[O:7][CH:6]=[N:5][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].I[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[CH2:1]([C:3]1[O:7][C:6]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[N:5][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: CCOC(=O)c1ncoc1CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)oc1CC
Temperature: 100 °C
Reaction time: 13 h
Yield: 37.2 %

Procedure:
Dioxane (30 mL) was added to ethyl 5-ethyl-1,3-oxazole-4-carboxylate (described in Armarego, Wilfred L. F.; Taguchi, Hiroyasu; Cotton, Richard G. H.; Battiston, Sandra; Leong, Lillian; Eur. J. Med. Chem. Chim. Ther.; 22; 1987; 283-292, 1.69 g, 10 mmol), 1-iodo-4-nitrobenzene (2.74 g, 11 mmol), palladium acetate (179.6 mg, 0.8 mmol), tris(2-methylphenyl)phosphine (0.49 g, 1.6 mmol) and cesium carbonate (3.25 g, 10 mmol), and the mixture was stirred at 100° C. for 13 hours. Water was added, followed by extraction with ethyl acetate and washing with brine. This was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=5/1, 3/1, 2/1) to obtain 1.08 g of the title compound as a colorless solid (37%).
Reaction SMILES: [OH-].[K+].CS(C)=O.[N:7]1([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:23]4[NH:24][C:25]5[C:30]([CH:31]=4)=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:21][N:22]=3)[N:19]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:32]I>O>[N:7]1([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:23]4[N:24]([CH3:32])[C:25]5[C:30]([CH:31]=4)=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:21][N:22]=3)[N:19]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CI
Reactant: c1ccc2[nH]c(-c3nnc4ccc(N5CCCCCC5)nn34)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(-c2nnc3ccc(N4CCCCCC4)nn23)cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of potassium hydroxide (98 mg) and DMSO (5 ml), 6-azepan-1-yl-3-(1H-indol-2-yl)-1,2,4-triazolo[4,3-b]pyridazine (501 mg) was added, and the mixture was stirred at room temperature for 30 minutes, and then combined with methyl iodide (0.15 ml) and then stirred for further 2 hours at room temperature. The reaction mixture was combined with water, and the resultant solids were collected by filtration, washed with a solvent a mixture of water and methanol, and then purified by silica gel column chromatography (eluent: chloroform: methanol=99:1). The resultant crude crystals were recrystallized from ethanol to obtain 6-azepan-1-yl-3-(1-methylindol-2-yl)-1,2,4-triazolo[4,3-b]pyridazine (40 mg) as colorless crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[N:7]=[C:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])=O.[CH3:23][NH2:24]>CO>[CH3:23][NH:24][C:3]([C:5]1[N:6]([CH3:22])[N:7]=[C:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])=[O:2]
Reactant: CN
Reactant: COC(=O)c1c2cccc(-c3ccc(Cl)cc3Cl)c2nn1C
Solvent: CO
Product: CNC(=O)c1c2cccc(-c3ccc(Cl)cc3Cl)c2nn1C
Yield: 88 %

Procedure:
A solution of 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole-3-carboxylic acid methyl ester (35b; 0.050 g, 0.15 mmol) in 4 mL of a 2 M solution of methylamine in methanol was stirred for 6 d, then concentrated to a white solid. Column chromatography (0→45% EtOAc/hexanes) afforded of 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole-3-carboxylic acid methylamide (35d; 0.044 g; 88%).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.[Cl:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([N:26]=[C:27]=[O:28])=[O:25]>C1(C)C=CC=CC=1>[F:14][C:11]([F:12])([F:13])[C:5]1([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[S:3][C:2]([NH:1][C:27]([NH:26][C:24](=[O:25])[C:23]2[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=2[Cl:21])=[O:28])=[N:6]1
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1ccccc1Cl)NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) was dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.0 g), and 2-chlorobenzoylisocyanate (0.4 g) which is a starting compound was added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[CH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([Cl:24])=[CH:19][N:18]=1>C(N(CC)CC)C.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.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:19]2[C:20]([Cl:24])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2nc(Cl)ncc2Cl)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (1.73 g), 2,4,5-trichloro-pyrimidine (0.86 mL), Pd(PPh3)2Cl2 (105 mg), and copper iodide (29 mg) in triethylamine (15 mL) under an argon atmosphere is heated in a microwave oven at 100° C. for 40 min. The solvent is evaporated in vacuo and 1 N citric acid is added. The mixture is extracted with dichloromethane and the combined extracts are washed with water, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 85:15→80:20) to give the title compound. LC (method 7): tR=1.55 min; Mass spectrum (ESI+): m/z=356 [M+H]+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[CH2:29]([N:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([N:26]2[CH2:27][CH2:28][N:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][CH3:15])[CH2:24][CH2:25]2)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccccc1N1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium triacetoxyborohydride (21.2 g) was added portionwise to a stirred solution of 1-(2-methoxyphenyl)piperazine (commercially available, 19.23 g) and 1-benzyl-4-piperidone (commercially available, 18.93 g) in CH2Cl2 (300 mL) at room temperature, followed by glacial acetic acid (6 mL). The resulting mixture was stirred at room temperature for 24 hours. The reaction was made basic by careful addition of saturated aqueous NaHCO3. The organic layer was separated, washed with brine, dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator to give the desired product (20.65 g) as an off-white solid which was used without further purification. The compound was characterized as the dihydrochloride salt, which was formed by dissolving the free base in ethanol and treating it with an excess of 1 N HCl/Et2O to give a white solid, which was collected by vacuum filtration, washed with Et2O and dried in vacuo; MP. 238-242° C.; MS (ES) m/z (relative intensity) 366 (M+H)+ (100).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>O1CCOCC1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: C1CNCCN1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: C1COCCO1
Product: Nc1c(F)c(N2CCNCC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
In the same manner as described in Example 1 (1), a mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, piperazine, and dioxane was refluxed for 5 hours to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 263°-264° C.
Reaction SMILES: BrC1C(O)=C(C(CSC2C=CC=CC=2OC)=CC=1)C(OC)=O.[Br:23][C:24]1[C:25]([O:36][CH3:37])=[C:26]([C:31]([CH2:34]Br)=[CH:32][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28].[SH:38][C:39]1[CH:40]=[C:41]([OH:45])[CH:42]=[CH:43][CH:44]=1>>[Br:23][C:24]1[C:25]([O:36][CH3:37])=[C:26]([C:31]([CH2:34][S:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([OH:45])[CH:40]=2)=[CH:32][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28]
Reactant: Oc1cccc(S)c1
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Agent: COC(=O)c1c(CSc2ccccc2OC)ccc(Br)c1O
Product: COC(=O)c1c(CSc2cccc(O)c2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 82, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and 3-mercaptophenol and used without further characterization.
Reaction SMILES: [CH3:1][Si:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][O:5][C:6](=[O:25])[CH:7]([NH:20][C:21]([O:23][CH3:24])=[O:22])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:19])=[CH:11][CH:10]=1.C1C=CC([I+][C:35]2[C:40]([C:41]([O-:43])=[O:42])=[CH:39][CH:38]=[CH:37][CH:36]=2)=CC=1.Cl>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:24][O:23][C:21]([NH:20][CH:7]([C:6]([O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:26])[CH3:27])=[O:25])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([NH:19][C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:40]=2[C:41]([OH:43])=[O:42])=[CH:11][CH:10]=1)=[O:22]
Reactant: O=C([O-])c1ccccc1[I+]c1ccccc1
Reactant: COC(=O)NC(Cc1ccc(N)c2ccccc12)C(=O)OCC[Si](C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)NC(Cc1ccc(Nc2ccccc2C(=O)O)c2ccccc12)C(=O)OCC[Si](C)(C)C
Temperature: 100 °C

Procedure:
A mixture of 3-(4-amino-naphthalen-1-yl)-2-methoxycarbonylamino-propionic acid 2-trimethylsilanyl-ethyl ester (0.93 g, 2.40 mmol), diphenyliodonium-2-carboxylate (1.22 g, 3.8 mmol, 1.5 eq) and copper(II) acetate (25 mg, 0.14 mmol, 0.06 eq) in N,N-dimethylformamide (25 mL) was heated to 100° C. for 14 hours, then cooled to room temperature. The mixture was acidified to a pH <3 with 1N HCl, extracted with ethyl acetate (3×35 mL). The combined organic layers were washed with 1N HCl (1×25 mL), water (1×25 mL), brine (1×25 mL), and dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified on silica gel eluting with 4:1 toluene/ethyl acetate to provide the titled compound. MS ESI(−)) m/e 507 (M−H)−.
Reaction SMILES: [CH:1]1([C:4]2[N:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:7]3=[N:8][C:9]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=4)[N:11]=[C:6]3[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+].O.Cl>CCO>[CH:1]1([C:4]2[N:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:7]3=[N:8][C:9]([C:19]4[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=4)=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=4)[N:11]=[C:6]3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CCCCCCn1c(C2CC2)cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nc3cc(C4CC4)n(CCCCCCC(=O)O)c3nc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 7-(6-cyclopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate (Step 6) (230 mg, 0.464 mmol) in EtOH (4 ml) was treated with 2M NaOH (0.696 ml, 1.392 mmol) and stirred at room temperature for 16 hours. The reaction mixture was added to water (50 ml) and the pH was adjusted to pH 1 by addition of 2M HCl. The resulting suspension was filtered, washed with water (×3) and dried under vacuum. The resultant residue was dissolved in EtOH (minimal) and excess water added. The resultant aqueous was then extracted with DCM (×3), and the organic solvent removed under reduced pressure. The resultant residue was then taken in diethyl ether, sonicated and the solvent removed under reduced pressure. Further diethyl ether was added, sonicated and the solvent removed under reduced pressure. The resultant residue was dissolved in EtOAc (minimal) and excess iso-hexane was added. The resultant suspension was filtered, the filter cake washed with iso-hexane (×4) and dried to afford the titled compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)(O)[OH:4].[H][H]>[Pd].C(O)C>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH:3]([OH:4])[C:2]([F:1])([F:15])[F:16])=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(C(O)(O)C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C(O)C(F)(F)F)cc1
Yield: 100 %

Procedure:
A mixture of 2,2,2-trifluoro-1-(4-nitro-phenyl)-ethane-1,1-diol (1.1 g, 4.6 mmol), palladium on carbon (100 mg, 10%), and ethanol (50 ml) was treated with hydrogen gas on a Parr shaker (50 psi) for 1 hour. The mixture was filtered through celite under suction and the filtrate was concentrated under reduced pressure to afford 1-(4-amino-phenyl)-2,2,2-trifluoro-ethanol (100% yield).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]=[C:11]([CH2:26][CH2:27][OH:28])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29](N(CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.C[O-].[Na+]>ClCCl.CC(C)=O>[CH2:19]([NH:18][C:13]1[C:14]([N+:15]([O-:17])=[O:16])=[C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=[C:11]([CH2:26][CH2:27][O:28][CH3:29])[N:12]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1c(NCc2ccccc2)cc(CCO)nc1NCc1ccccc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: C[O-]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COCCc1cc(NCc2ccccc2)c([N+](=O)[O-])c(NCc2ccccc2)n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
2-(4,6-Bis-benzylamino-5-nitro-pyridin-2-yl)-ethanol (134 mg, 35 mmol), was suspended in a mixture of dichloromethane (15 ml) and triethylamine (59 μl, 0.43 mmol) and the solution cooled to 5° C. in an ice bath. Methanesulphonyl chloride (33 μl, 0.43 mmol) was added and the reaction mixture stirred at ambient temperature for 1 h. A further 10 ml DCM was added, the organics washed with 2×K2CO3 (10% aq solution), dried and concentrated to afford a crude oil. The intermediate mesylate was suspended in acetone (20 ml) and sodium methoxide added (96 mg, 1.7 mmol), heating the mixture at reflux for 1 h. Residual solvent was removed in vacuo, DCM added and the solution washed with 2×H2O. The combined organics were dried over MgSO4, concentrated and purified by column chromatography on silica, eluting with Pent:EtOAc, 8:1 to 4:1 to afford the title compound as a yellow oil, (68 mg, 47%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1.[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24]Br)[CH3:21].C(OCC)(=O)C>CN(C=O)C.O>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:17][CH2:24][CH:23]([O:26][CH2:27][CH3:28])[O:22][CH2:20][CH3:21])=[CH:14][CH:13]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CCOC(CBr)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(COCc1ccc(Br)cc1)OCC
Reaction time: 0.08 h
Yield: 55.8 %

Procedure:
Sodium bis(trimethylsilyl)amide (12.1 mL, 1 N in THF) is added to a stirred solution of 4-bromo-benzylalcohol (2.05 g, 11.0 mmol) in dry DMF (7 mL) at ambient temperature. The mixture is stirred for 5 min before it is treated with bromoacetaldehyde diethyl acetal (1.99 mL, 13.2 mmol). The resultant mixture is allowed to stir at ambient temperature for 20 hours. Ethyl acetate (60 mL) and water (60 mL) are added to the mixture. The organic layer is separated, washed with half-saturated brine, dried, filtered and concentrated. After MPLC separation on silica (gradient 0-8% ethyl acetate in hexane), 1.86 g (56% yield) title compound is obtained as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:17][C:18]([CH3:22])([OH:21])[C:19]#[CH:20]>ClCCl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[NH2:1][C:2]1[C:7]([C:20]#[C:19][C:18]([CH3:22])([OH:21])[CH3:17])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1I
Reactant: C#CC(C)(C)O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
A suspension of 2-amino-5-bromo-3-iodopyridine (10.0 g, 33.5 mmol), bis-(triphenylphosphine)-palladium(II)-dichloride (117 mg, 0.17 mmol), copper(I)iodide (79 mg, 0.41 mmol) and triethylamine (6.1 mL, 43.5 mmol) in dichloromethane (40 mL) was treated at 23 to 30° C. within 1 to 2 hours with a solution of 1,1-dimethyl-2-propyn-1-ol (3.70 g, 44 mmol) in dichloromethane (10 mL) and the resulting mixture was stirred at 25° C. for 3 hours. The mixture was diluted with dichloromethane (20 mL) and washed with water (2×50 mL). The organic phase was then treated with 1 M HCl (80 mL). The layers were separated and the organic layer was extracted with 1 M HCl (20 mL). The combined product containing aqueous layers were washed with dichloromethane (2×10 mL). The pH of the aqueous layer was adjusted to pH 7-9 by the drop wise addition of sodium hydroxide solution (28% in water, 18 g). The resulting suspension was stirred at 20° C. for 2 hours and the crystals were then filtered off and washed with water (2×20 mL). The wet crystals were dried at 50° C./<30 mbar affording 6.99 g (82%) of 4-(2-amino-5-bromo-pyridin-3-yl)-2-methyl-but-3-yn-2-ol as a melted mass with a purity of 99.5% (HPLC, area %). 1H NMR (400 MHz, CDCl3): δ ppm 1.63 (s, 6H); 4.0 (br., 3H); 7.59 (d, J=2.4, 1H); 8.03 (d, J=2.4, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.CC([O-])=O.[Na+].[Br:16]Br>CC(O)=O>[NH2:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][C:5]([Br:16])=[CH:6][N:7]=1
Reactant: NC(=O)c1nccnc1N
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)c1nc(Br)cnc1N
Temperature: 50 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a stirred solution of 3-aminopyrazine-2-carboxamide (1 g, 7.24 mmol, prepared according to International Patent Application Publication No. WO2011054922) and NaOAc (200 mg, 2.44 mmol) in HOAc (15 mL) was added Br2 (0.45 mL) dropwise at 0° C. for 1 hour, and then it was stirred at 50° C. for 8 hours. After the mixing, it was poured into ice-water and filtrated, the crude product of 3-amino-6-bromopyrazine-2-carboxamide as brown solid (1.5 g, yield: 95%) was obtained. 1H-NMR (DMSO-d6, 400 MHz) δ 8.30 (s, 1H), 7.93 (s, 2H), 7.66 (s, 2H). MS (M+H)+: 217/219.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][C@H:12]1[C:18]([NH2:20])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][C@H:12]1[C:18]#[N:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: N#C[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of benzyl-(2S)-2-aminocarbonyl-4,4-difluoropyrrolidine-1-carboxylate and triethylamine (2.1 eq.) in dichloromethane was cooled to 0° C. and trifluoroacetic anhydride (1.1 eq.) was added dropwise under nitrogen. Stirring was continued for 1 hour allowing the mixture to reach room temperature. Volatiles removed in vacuo and residue taken up in ethyl acetate, washed with HCl 1N, brine and dried over Na2SO4. Evaporation gave title compound as brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:25]C(=O)C)=[C:6]2[C:10]=1[C:9](=[O:11])[C:8]([OH:23])([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[O:21][CH3:22])[C:7]2=[O:24]>Cl.CO.C(Cl)Cl>[NH2:25][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[C:10]2[C:6]=1[C:7](=[O:24])[C:8]([OH:23])([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[O:21][CH3:22])[C:9]2=[O:11]
Reactant: COc1cc(C(C)C)ccc1C1(O)C(=O)c2c(N)ccc(NC(C)=O)c2C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(C)C)ccc1C1(O)C(=O)c2c(N)ccc(N)c2C1=O
Yield: 235 %

Procedure:
N-(7-amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (45 mg, 0.10 mmol) was completely dissolved in 6M HCl (1.4 ml) and methanol (0.1 ml), followed by heating for 90 min at 80. The reaction mixture was diluted with methylene chloride, extracted with 2N NaOH aqueous solution, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:1) to afford the title compound (80 mg, 200%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].C1C(=O)N([Br:20])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[I:1]
Reactant: COC(=O)c1ccc(C)c(I)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(I)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
Into a 100-mL round-bottom flask, was placed a mixture of methyl 3-iodo-4-methylbenzoate (compound 5.3, 3.00 g, 10.9 mmol) in CCl4 (50 mL), NBS (2.9 g, 16.3 mmol), azobisisobutyronitrile (360 mg, 2.19 mmol) and potassium carbonate (1.65 g, 11.9 mmol). The resulting mixture was stirred overnight at 70° C., then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and the mixture was washed with brine (2×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:20) as the eluent to yield 3.0 g (78%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[N:10]2)[N:3]=1.[CH3:18][O-:19].[Na+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[N:10]2)[N:5]=[C:6]([O:19][CH3:18])[CH:7]=1
Reactant: C[O-]
Reactant: FC(F)(F)c1ccn(-c2nc(Cl)cc(Cl)n2)n1
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)nc(-n2ccc(C(F)(F)F)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirred solution of compound 304 (1 g, 3.53 mmol) in MeOH (10 mL) at 0° C. was added NaOMe (760 μL) dropwise. The mixture was stirred at room temperature for 2 hrs. Methanol was evaporated. The residue was dissolved in DCM, washed sequentially with water and brine. Organics were dried over Na2SO4 filtered, concentrated under reduced pressure, and purified by silica gel chromatography to yield compound 305 as a white solid in 68% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 4.11 (s, 3H), 6.71-6.72 (m, 2H), 8.58 (dd, J=2.78 Hz and J=1.00 Hz, 1H); 19F NMR (CDCl3, 376 MHz) δ (ppm) −62.54 (s, 3F).