Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:22]=[N:23][N:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:25]=2[CH2:26][OH:27])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:34]([OH:36])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.N1(O)C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>C(#N)C.O.C(N(CC)CC)C>[OH:27][CH2:26][C:25]1[N:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:23]=[N:22][C:21]=1[C:19]([N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C@H:12]1[CH2:11][C@@H:10]([C:34]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[O:36])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13]1)=[O:20]
Reactant: CC(C)CN(C(=O)c1nnn(-c2ccccc2)c1CO)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)CN(C(=O)c1nnn(-c2ccccc2)c1CO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[5-(hydroxymethyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (2.18 g), 5 morpholine (0.46 ml), 1H-benzotriazol-1-ol (330 mg) and triethylamine (1.5 ml) were dissolved in acetonitrile (20 ml), WSC.HCl (1.25 g) was added and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (2.35 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[CH:27]=1)[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=[CH:10]1)(=O)=O.[C:33](#[N:35])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:19]([O:18][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[N:9]([C@@H:8]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[CH:27]=1)[CH2:7][CH2:6][C:33]#[N:35])[CH:10]=[CH:11]2)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC#N
Reactant: CS(=O)(=O)OCC[C@H](c1cccc(Br)c1)n1ccc2cccc(OCc3ccccc3)c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: N#CCC[C@H](c1cccc(Br)c1)n1ccc2cccc(OCc3ccccc3)c21
Yield: 74 %

Procedure:
A solution of (3R)-3-(3-bromophenyl)-3-(7-benzyloxyindol-1-yl)propan-1-yl methanesulfonate (2.50 g, 4.86 mmol prepared as in Example 3, step (i)) and tetrabutylammonium cyanide (1.96 g, 7.30 mmol) in dry acetonitrile (40.0 ml) under nitrogen was heated under reflux for 24 h. The cooled solution was evaporated to yield an orange/brown oil which was taken up in ethyl acetate (200 ml), washed with water (3×100 ml), dried (Na2SO4) and the solvent removed in vacuo. Column chromatography (ethyl acetate-light petroleum (b.p. 40-60° C.), 1:4) gave the title compound as a pale yellow oil (1.60 g, 74%). [α]D19 −129 (c=0.005 gml−1, CHCl3); νmax (thin film)/cm−1 3064, 3033, 2932, 2872, 2247 (CN), 1575; δH (270 MHz) 2.10 (2H, m, 2×propyl 3-H); 2.38 (2H, m, 2×propyl 2-H); 5.09 (2H, q, CH2Ph, 2J=10.9 Hz); 6.39 (1H, dd, propyl 1-H, 3J1,2=9.7, 3J1,2′=5.8 Hz); 6.55 (1H, d, 3-H, 3J3,2=3.3 Hz); 6.70 (1H, d, 6-H, Jo=7.6 Hz); 6.83 (1H, d, 4-H, Jo=7.6 Hz); 7.00 (2H, m, 5-H, 5′-H); 7.05 (1H, d, 2-H, 3J2,3=3.0 Hz); 7.15 (1H, s, 2′-H); 7.21 (1H, d, 6′-H, Jo=8.0 Hz); 7.30 (1H, d, 4′-H, Jo=8.6 Hz); 7.38 (5H, m, 5ArH).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[CH:17]=[C:16]([OH:31])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:32]([O:34]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:37]>C1COCC1>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[CH:17]=[C:16]([OH:31])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:32](=[O:34])[NH2:37])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cc(-c3ccc(C(F)(F)F)cc3)cc1n2Cc1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cc(-c3ccc(C(F)(F)F)cc3)cc1n2Cc1ccccc1
Yield: 19 %

Procedure:
A solution of the 9-[(phenyl)methyl]-2-(4-trifluoromethylphenyl)-4-hydroxy-5-carbomethoxy carbazole (1.10 g, 2.31 mM) in 35 ml THF and 140 mL concentrated aqueous ammonium hydroxide was sonicated for 6 hours at 30-40° C. The precipitated solid was filtered and washed with water. Trituration with Et2O, then with 2:1 Et2O/CH2Cl2 afforded 0.20 g (19%) of the 9-[(phenyl)methyl]-2-(4-trifluoromethylphenyl)-4-hydroxy-5-carbamoyl carbazole. 1H NMR (DMSO-d6) δ10.8 (s, 1H), 8.9 (bs, 1H), 8.45 (bs, 1H), 8.0 (d, J=8 Hz, 2H), 7.8 (d, J=8 Hz, 2H), 7.6 (s, 1H), 7.5 (m, 2H), 7.3-7.1 (m, 6H), 7.0 (s, 1H), 5.8 (s, 2H). MS (ES) m/e 444, 461.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.CO.[Cl-].[NH4+]>[Zn].C(OCC)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCOCC
Product: CN1CCN(Cc2ccc(N)cc2)CC1
Yield: 77.3 %

Procedure:
1-methyl-4-(4-nitrobenzyl)-piperazine (F652-01, 4.67 g, 19.9 mmol), methanol (100 mL), zinc powder (6.5 g, 99.3 mmol) and ammonium chloride (4.3 g, 79.5 mmol) were placed in a reaction vessel and heated for 2 hours under reflux. After returning to room temperature, the reaction mixture was filtered through Celite. The solvent of the filtrate was distilled off under reduced pressure to obtain a solid. Diethyl ether was added to the solid, and insoluble components were removed by filtration. 4-(4-methylpiperazin-1-ylmethyl)phenylamine (F652-02, white solid, 3.16 g, 77%) was obtained by removing the solvent of the filtrate by distillation.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[O-].[Na+].O.[C:18]([O:25][CH3:26])(=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21]>[Cu]Br>[C:4]([C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[CH:19]([C:18]([O:25][CH3:26])=[O:24])[C:20]([O:22][CH3:23])=[O:21])([OH:6])=[O:5]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: COC(=O)CC(=O)OC
Agent: [Cu]Br
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C(C(=O)OC)c1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
2-Chloro-4-nitrobenzoic acid (7.5 g, 37.2 mmol) was dissolved in deaerated dimethyl malonate (90 mL). Copper (I) bromide (0.54 g, 3.7 mmol) and sodium methoxide (4.83 g, 89.4 mmol) were added to the solution. The mixture was stirred at room temperature for 15 minutes, and then stirred at 70 to 75° C. overnight. After the reaction solution was allowed to return to room temperature, water was added thereto and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (7.0 g, 68%).
Reaction SMILES: [C-]#N.[Na+].[Cl:4][C:5]1[N:6]=[CH:7][C:8]2[CH:13]=[C:12]([CH2:14][OH:15])[N:11]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:9]=2[N:10]=1.[CH3:21][NH:22][CH3:23].N[C@H](C(O)=O)C>[O-2].[Mn+4].[O-2].CN(C)C=O>[Cl:4][C:5]1[N:6]=[CH:7][C:8]2[CH:13]=[C:12]([C:14]([N:22]([CH3:23])[CH3:21])=[O:15])[N:11]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[C:9]=2[N:10]=1
Reactant: OCc1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CNC
Agent: [Mn+4]
Agent: C[C@H](N)C(=O)O
Agent: [C-]#N
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reaction time: 0.5 h

Procedure:
A dry, nitrogen-flushed ACE-100 L Reaction vessel is charged with 97.3 g of sodium cyanide, 2,500 g of (2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol, A1e, 16,680 g (19.5 L) of dimethylamine, Ala (2.0M solution in THF), and 28,320 g (30.0 L) of anhydrous N,N-dimethylformamide. The mixture is stirred at 20±3° C. for 15 min 2.06 kg of manganese(IV) oxide is then added. The dark slurry is stirred for 30 min and 12.36 Kg of manganese (IV) oxide is added in three portions (1st portion: 2.06 kg; 2nd portion: 4.12 g, and 3rd portion: 6.18 kg) every 30 min. After the last portion has been added, the sample is held for 1 h and then 6.18 kg of manganese(IV) oxide is added. The sample is held for 1 h. The reaction mixture is then sampled. The reaction is considered complete if the starting material, A1c is ≦1.0±0.5% as determined by HPLC analysis. The reaction mixture is then filtered through a pad of celite to remove manganese (IV) oxide. The reactor and cake are rinsed with 23 L of ethyl acetate. The filtrate and distil are combined under reduced pressure (45±3° C., 20 mbar) to remove THF, dimethylamine and ethyl acetate. The sample is further distilled under reduced pressure (70±5° C., 5 mbar) to remove DMF. The concentrate is diluted with 35 L of ethyl acetate. The resulting dark solution is washed with aqueous ferrous sulfate solution (1 kg of FeSO4.7H2O in 14 L of water), 15 L of water and finally 15 L of 10% aqueous NaCl solution. The phases are separated after each wash. The organic phase is distilled (45° C., 50 mbar) to azeotropically remove water. The resulting crude A1 (2,788 g of a dark, thick, semi-solid residue) can be used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2Br)[OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([OH:15])[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccncc2Br)CC1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccncc2)CC1
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of the above alcohol (610 mg, 1.6 mmol) in MeOH (5 mL) in a Parr flask was added 10% Pd/C (100 mg) under N2. The mixture was hydrogenated at room temperature under 1.5 atm H2 for 1 h. 3N NaOH (5 mL) was added and the mixture was extracted with CHCl3 (20 mL×2). The solution was filtered through a short pad of Celite® to give the 4-(hydroxy-pyridin-4-yl-methyl)-piperidine-1-carboxylic acid tert-butyl ester (380 mg, 81%) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:21]([F:37])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13].[CH2:38]([SH:40])[CH3:39].C(N(CC)CC)C.Cl>CN(C)C=O.O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22]([S:40][CH2:38][CH3:39])[C:21]([F:37])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13]
Reactant: CCS
Reactant: CCOC(=O)CC(=O)c1cc(F)c(OS(=O)(=O)c2c(C)cc(C)cc2C)nc1Nc1ccc(F)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1cc(F)c(SCC)nc1Nc1ccc(F)cc1F
Yield: 67.3 %

Procedure:
In 1 ml of N,N-dimethylformamide was dissolved 100 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-trimethylbenzenesulfonyloxy)nicotinoyl]acetate, and 17 mg of ethanethiol and 28 mg of triethylamine were added thereto, after which the resulting mixture was subjected to reaction at room temperature for 4 hours. Subsequently, to the reaction mixture were added 3 ml of ethyl acetate and 3 ml of water, and the pH thereof was adjusted to 1.0 with 2N hydrochloric acid. The organic layer was separated, washed successively with 2 ml of water and 2 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant:benzene-n-hexane (1:2 by volume)] to obtain 50 mg (yield 67.4%) of ethyl 2-[2-(2,4-difluorophenylamino)-6-ethylthio-5-fluoronicotinoyl]acetate. The physical properties of this compound were identical with those of the compound obtained in Example 19.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:3]=1[NH2:4].[CH3:20][O:21][C:22]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[C:27]([O:34][CH3:35])[C:23]=1[C:24](O)=[O:25].C(N(CC)CC)C.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>ClCCl>[CH3:19][C:5]1[CH:6]=[C:7]([C:9]([F:18])([C:10]([F:12])([F:13])[F:11])[C:14]([F:15])([F:16])[F:17])[CH:8]=[C:2]([CH3:1])[C:3]=1[NH:4][C:24](=[O:25])[C:23]1[C:27]([O:34][CH3:35])=[CH:28][CH:29]=[C:30]([N+:31]([O-:33])=[O:32])[C:22]=1[O:21][CH3:20]
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1C(=O)O
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])c(OC)c1C(=O)Nc1c(C)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a solution of 2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-aniline (145 mg, 0.5 mmol) and 2,6-dimethoxy-3-nitrobenzoic acid (136 mg, 0.6 mmol) in dichloromethane (10 ml) was added triethylamine (210 μl, 1.5 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride “BOP-Cl” (153 mg, 0.6 mmol). The reaction mixture was heated to reflux for 48 hours. The reaction mixture was cooled to ambient temperature and quenched by the addition of a saturated sodium bicarbonate solution (10 ml). The phases were separated, the organic phase was dried over sodium sulfate and concentrated. Purification by chromatography over silica gel (eluent: hexane/ethyl acetate 2:1) gave N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-2,6-dimethoxy-3-nitrobenzamide (222 mg, 89% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[BH4-].[Na+].C(O)(=O)C.[NH4+].[Cl-]>C1COCC1>[CH3:2][NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:1]
Reactant: c1ccc2ocnc2c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1ccccc1O
Temperature: 0 °C

Procedure:
1 g of benzoxazole was dissolved in 20 ml of THF. 0.9 g of NaBH4 were added under nitrogen and stirring. The suspension was cooled to 0° C. and 0.86 ml of acetic acid dissolved in 5 ml THF were slowly added, keeping the reaction temperature below 5° C. The reaction was stirred at 0° C. for 30 minutes and for further 12 hours at room temperature. The reaction mixture was again cooled to 0° C. and 50 ml of sat. NH4Cl solution were added carefully. The phases were separated and the aqueous layer extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and filtered. Removal of the solvent afforded 0.97 g (of pure 2-(N-methylamino)-phenol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17](COCC[Si](C)(C)C)[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][NH:17][C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Reaction time: 4 h
Yield: 40.6 %

Procedure:
To a stirred solution of 2-(6-chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.080 g, 165 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1.88 g, 1.27 mL, 16.5 mmol). The reaction mixture was stirred for 4 h, then was concentrated in vacuo. The residue was diluted with dichloromethane and concentrated in vacuo again, then was suspended in dichloromethane and ethylenediamine (743 mg, 0.835 mL, 12.4 mmol) added. After 15 h the mixture was concentrated, triturated with water and the solid obtained by filtration was dried and purified by chromatography (silica, SiliCycle 25 g cartridge, 0-5% methanol in dichloromethane, gradient over 15 min) to give 2-(6-chloro-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (24 mg, 67.0 μmol, 41%) as a pale yellow powder. MS (M+Na)+=377; 1H NMR (DMSO-d6) δ: 13.16 (br. s, 1H), 12.39 (br. s, 1H), 9.12 (s, 1H), 8.39 (d, J=8.7 Hz, 1H), 8.17 (d, J=2.6 Hz, 1H), 8.10 (d, J=7.9 Hz, 1H), 7.53 (s, 1H), 7.09 (dd, J=9.1, 1.0 Hz, 1H), 4.18-4.41 (m, 1H), 1.31 (d, J=6.4 Hz, 6H)
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S1C=CC=C1[Cl:17].CCOCC>CN(C)C=O>[N+:1]([C:4]1[O:8][C:7]([C:9]([Cl:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Reactant: Clc1cccs1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cl)c1ccc([N+](=O)[O-])o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3.00 g. of 5-nitro-2-furan-carboxylic acid and 2.06 ml. of thienyl chloride in 50 ml. ether is added 0.45 ml. of dimethyl formamide. The reaction mixture is stirred overnight, under nitrogen, at room temperature. The ether solution is then decanted and the solvent removed to yield 5-nitro-2-furancarboxylic acid chloride, which is then dissolved in 50 ml. ether at 0° . To this solution is added, under nitrogen, 2.06 g. of cyclopropanemethyl alcohol and 3.1 of pyridine. The reaction mixture is allowed to warm to room temperature and is stirred for six days. Ether and water is added to the reaction mixture, the ether layer is decanted, and the aqueous phase is extracted once with ether. The combined organic phases are washed with 2N sulfuric acid, sodium carbonate, water, saturated copper sulfate, and brine, dried over calcium sulfate and the solvent removed to give 3.36 g. of cyclopropanemethyl 5-nitro-2-furancarboxylate, melting point 78°-80°.
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][OH:21])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl[CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31]>>[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][O:21][CH2:29][C:30](=[O:31])[N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1c2ccc(CC(=O)NO)ccc-2c(C(=O)OCC)c1N
Reactant: O=C(CCl)N1CCCC1
Agent: [Na]
Product: CCOC(=O)c1c2ccc(CC(=O)NOCC(=O)N3CCCC3)ccc-2c(C(=O)OCC)c1N
Yield: 24 %

Procedure:
In an analogous manner to that described in Example 1, from diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and N-chloroacetyl-pyrrolidine the title compound of m.p. 168-170° C. is obtained in 24% yield.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1([CH2:13][CH2:14]O)[CH2:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:10]1([CH2:13][CH2:14][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:12][CH2:11]1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCC1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OCCC2CC2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 75.6 %

Procedure:
To a mixture of 4-hydroxybenzaldehyde (2.84 g), 2-cyclopropylethanol (2.00 g), triphenylphosphine (6.09 g) and tetrahydrofuran (100 mL), diethyl azodicarboxylate (2.2 mol/L, solution in toluene, 10.5 mL) was added and the mixture was stirred at room temperature for 4 days. After concentrating the reaction mixture under reduced pressure, ethyl acetate (7.50 mL) and n-hexane (143 mL) were added and the mixture was stirred at room temperature for 15 minutes. The precipitate was removed by filtration through Celite (registered trademark). The filtrate was concentrated under reduced pressure and, thereafter, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-50:50) to give the titled compound as a yellow oil (3.34 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([NH:14][CH:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH2:16]1)[CH2:7]2>[Pd].C(O)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][CH:2]=[C:3]2[C:8]=1[CH2:7][N:6]([NH:14][C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1)[CH2:5][CH2:4]2
Reactant: COc1ccc(Br)c2c1CN(NC1C=CN=CC1)C=C2
Agent: [Pd]
Solvent: CCO
Product: COc1cccc2c1CN(Nc1ccncc1)CC2
Yield: 40.9 %

Procedure:
A mixture of 5-bromo-3,4-dihydro-8-methoxy-1H-isoquinolin-2-yl-4-pyridinylamine (0.8 g), ethanol (75 ml) and 5% palladium-on-carbon (0.1 g) was hydrogenated at 55 psi overnight in a Parr shaker at ambient temperature. The reaction mixture was filtered through a pad of celite, the pad was washed with methanol, and the filtrate was concentrated. Aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel on a Chromatotron, eluting with 1% triethylamine/5% methanol/94% ethyl acetate. The appropriate fractions were collected and concentrated. The residue was crystallized in hot ethyl acetate to give 0.25 g (41%) of product, mp 170-171° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[N:16]=[N:17][N:18]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[CH:19]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:29])[CH:3]=1.[OH:30][C@:31]1([C:45]2[S:46][CH:47]=[CH:48][N:49]=2)[CH2:40][CH2:39][CH2:38][C:37]2[CH:36]=[C:35]([C:41]([O:43][CH3:44])=[O:42])[CH:34]=[CH:33][C:32]1=2.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.[F-].[Cs+].C(O)(=O)C(C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:30][C@:31]1([C:45]2[S:46][C:47]([C:2]3[CH:3]=[C:4]([CH3:29])[CH:5]=[C:6]([NH:8][C:9]4[CH:14]=[C:13]([C:15]5[N:16]=[N:17][N:18]([CH2:20][C:21]6[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=6)[CH:19]=5)[CH:12]=[CH:11][N:10]=4)[N:7]=3)=[CH:48][N:49]=2)[CH2:40][CH2:39][CH2:38][C:37]2[CH:36]=[C:35]([C:41]([O:43][CH3:44])=[O:42])[CH:34]=[CH:33][C:32]1=2
Reactant: COC(=O)c1ccc2c(c1)CCC[C@]2(O)c1nccs1
Reactant: COc1ccc(Cn2cc(-c3ccnc(Nc4cc(C)cc(Br)n4)c3)nn2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)C(=O)O
Product: COC(=O)c1ccc2c(c1)CCC[C@]2(O)c1ncc(-c2cc(C)cc(Nc3cc(-c4cn(Cc5ccc(OC)cc5)nn4)ccn3)n2)s1
Temperature: 100 °C
Yield: 33.5 %

Procedure:
To microwave vial were added 6-bromo-N-(4-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)-4-methylpyridin-2-amine (247 mg, 0.547 mmol), (R)-methyl 5-hydroxy-5-(thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (158 mg, 0.547 mmol), butyldi-1-adamantylphosphine (78 mg, 0.219 mmol), CsF (249 mg, 1.64 mmol), pivalic acid (95 μl, 0.821 mmol), and Pd(OAc)2 (24.6 mg, 0.109 mmol). The reaction was vacuum and purged with argon 3 times, then degassed 1,4-Dioxane (2.0 mL) was added and the reaction was heated to 100° C. for 16 h. The reaction was cooled to rt and diluted with EtOAc (20 mL). The reaction was filtered, concentrated and purified by silica gel chromatography using a gradient solvent system of 30-100% EtOAc/Hexanes. The product-containing fractions were collected and concentrated to give (R)-methyl 5-hydroxy-5-(5-(6-((4-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-4-methylpyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (121 mg, 34%) as a white foam. MS ESI calcd for C36H33N7O4S [M+H]+ 660, found 660.