Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=1[O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][O:9][C:8]1[CH:16]=[CH:17][C:18]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:19][C:7]=1[CH3:6])[CH3:15]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)COc1ccccc1C
Product: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1C
Temperature: 4 °C
Reaction time: 2 h

Procedure:
To a flask containing chlorosulfonic acid (15.0 mL, 226 mmol) at 4° C. was added ethyl (2-methylphenoxy)acetate A1a (10.0 g, 51.6 mmol) slowly. The mixture was stirred at 4° C. for 30 min and room temperature for 2 h, and then poured into ice water. The precipitated white solid was filtered, washed with water, and dried under vacuum overnight to provide 14.0 g (93%) of A1b as a white solid; 1H NMR (300 MHz, CDCl3) δ 7.87–7.84 (m, 2 H), 6.80 (d, J=9.5 Hz, 1 H), 4.76 (s, 2 H), 4.29 (q, J=7.1 Hz, 2 H), 2.37 (s, 3 H), 1.31 (t, J=7.1 Hz, 3 H); MS (ES) m/z: 315 (M+Na+).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:18])[CH2:12][CH2:13][C@H:14]([NH2:17])[CH2:15][F:16].[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(O)(=O)C>[C:19]([NH:17][C@H:14]([CH2:15][F:16])[CH2:13][CH2:12][C:11]([O:10][CH3:9])=[O:18])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CC[C@H](N)CF
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COC(=O)CC[C@@H](CF)NC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.26 ml of triethylamine and 2 ml of glacial acetic acid were mixed with 0.34 g of 4. The mixture was cooled to 0° C. and 0.21 ml of acetic anhydride was added drop-by-drop to the stirred mixture. The mixture was allowed to warm to room temperature and stirred for 30 minutes. The solvents were evaporated under reduced pressure, the residue was triturated with a mixture of ethyl acetate and ether and filtered. The filtrate was eluted through a florisil pad, using ethyl acetate as eluent. The solvent was evaporated under reduced pressure to give 6, as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5](C(OC)=O)=[C:4]([F:12])[CH:3]=1.[CH3:13][Mg+].[Br-].CC[O:18][CH2:19][CH3:20]>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:19]([OH:18])([CH3:20])[CH3:13])=[C:4]([F:12])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1F
Reactant: C[Mg+]
Reactant: CCOCC
Agent: [Br-]
Product: CC(C)(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of methyl 4-bromo-2-fluorobenzoate (12 g, 51.5 mmol) in anhydrous ether (140 mL) at 0° C. was added MeMgBr (3.0 M, 70 g) dropwise. The mixture was slowly warmed up to room temperature and stirred for 3 hours. The reaction was quenched by the addition of saturated NH4Cl and extracted with EtOAc (3×150 mL). The combined organic extracts were washed with brine, dried with Na2SO4 and evaporated to dryness. The mixture was purified by flash column chromatography (0–20% EtOAc in hexanes) to give the product (12 g, 95% yield). 1H NMR (300 MHz, CDCl3) δ: 1.62 (s, 6 H), 7.18–7.23 (m, 1 H), 7.25–7.28 (m, 1 H), 7.44–7.49 (m, 1 H).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]([C@@H:11]([C@H:13]([C:15]([O:17]CC)=O)[OH:14])[OH:12])([O:8]CC)=O.O>CO>[CH2:1]([NH:5][C:6](=[O:8])[C@@H:11]([C@H:13]([C:15]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:17])[OH:14])[OH:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Solvent: CO
Solvent: O
Product: CCCCNC(=O)[C@H](O)[C@@H](O)C(=O)NCCCC
Reaction time: 0.5 h
Yield: 56 %

Procedure:
N,N′-Di-n-butyl L-tartaramide was prepared by the reaction of n-butyl amine with diethyl L-tartrate. Diethyl L-tartrate (20.010 g, 1.0 eq) and HPLC grade methanol (40 mL) were weighed into a 250 mL round-bottomed flask equipped with a teflon coated magnetic stir bar. n-Butyl amine (14.906 g, 2.0 eq) was slowly poured into the stirring diethyl L-tartrate solution. Some fuming and a color change from water-white to pale yellow were observed. Additional methanol (10 mL) was used to rinse all of the amine into the reaction flask. After stirring the solution for 30 min, the flask was stoppered and refrigerated at approximately 45° F. (7° C.). The product crystallized out after 30 min of refrigeration; however, it was allowed to remain in the refrigerator for 3 days. The white needle-like crystals were filtered, washed with methanol (˜150 mL), washed with diethyl ether (2×30 mL), and dried under vacuum. The product was obtained in 56% yield (14.275 g, 54.8 mmole).
Reaction SMILES: C1COCC1.O.[O:7]1[CH2:12][CH2:11][O:10][C:9]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])=[CH:16][C:8]1=2.[OH-].[Na+].C(O)(=O)C>O>[O:7]1[CH2:12][CH2:11][O:10][C:9]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:23])[C:18]([OH:20])=[O:19])=[CH:16][C:8]1=2
Reactant: CCOC(=O)C(C)c1ccc2c(c1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the flask was added THF/H2O (1:1, 4 mL) followed by Ethyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-7-yl)propanoate (133 mg, 0.563 mmol) and NaOH (30 mg, 0.750 mmol) at room temperature. The reaction mixture was stirred for 16 hrs at room temperature. The mixture was diluted with H2O (20 mL) and acidified with acetic acid (4 mL, pH=4) then extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:26])[N:20]([CH2:22][C:23]([OH:25])=O)[N:21]=[C:8]2[N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[C:6]=1[CH3:37])=[O:4].[CH:38]([N:41]([CH:44]([CH3:46])C)[CH2:42]C)(C)C.CN(C(ON1N=NC2[CH:58]=[CH:59][CH:60]=[N:61][C:56]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C@@H:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)[N:9]2[C:19](=[O:26])[N:20]([CH2:22][C:23](=[O:25])[N:61]([CH2:60][CH2:59][CH2:58][CH2:46][CH2:44][N:41]([CH3:38])[CH3:42])[CH3:56])[N:21]=[C:8]2[N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=2)[C:6]=1[CH3:37])=[O:4]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CC(=O)O)c(=O)n2[C@@H]1c1ccc(C#N)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CC(=O)N(C)CCCCCN(C)C)c(=O)n2[C@@H]1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 29.9 %

Procedure:
Intermediate 26 (250 mg, 0.46 mmol) was dissolved in DMF (5 mL), and then diisopropylethylamine (240 μL, 1.4 mmol) and HATU (266 mg, 0.7 mmol) were added. The reaction mixture was stirred at RT for 40 minutes, then N,N,N-trimethylpentanediamine (288 mg, 2.0 mmol) in DMF (1 mL) was added, and stirring was continued for a further 18 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 4-8% (2 M NH3 in MeOH) in DCM followed by a gradient of 6-7% (2 M NH3 in MeOH) in DCM. The resulting residue was purified by MDAP to yield the title compound as an off-white solid (88 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[OH:12][C:13]1[CH:22]=[C:21]([O:23][CH:24]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:25])[CH:20]=[C:19]2[C:14]=1[CH:15]([CH2:39][CH2:40][C:41]#[N:42])[CH2:16][CH:17]1[CH2:38][CH2:37][CH2:36][CH2:35][N:18]12>C(OCC)(=O)C>[OH:12][C:13]1[CH:22]=[C:21]([O:23][CH:24]([CH2:26][CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH3:25])[CH:20]=[C:19]2[C:14]=1[CH:15]([CH2:39][CH2:40][CH2:41][NH2:42])[CH2:16][CH:17]1[CH2:38][CH2:37][CH2:36][CH2:35][N:18]12
Reactant: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)N1CCCCC1CC2CCC#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)N1CCCCC1CC2CCCN
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Under anhydrous conditions and a nitrogen atmosphere, to a solution of 190 mg. (5 mmole) lithium aluminum hydride in 50 ml. tetrahydrofuran at 10° C. is added dropwise a solution of 2.09 g. (5 mmole) dl-7-hydroxy-6-(2-cyanoethyl)-9-(5-phenyl-2-pentyloxy)-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a]quinoline in 25 ml. tetrahydrofuran. The mixture is stirred at room temperature for 6 hours after the addition. Ethyl acetate is added to quench the reaction, the solvent is evaporated in vacuo and the residue partitioned between water and methylene chloride. The organic extracts are dried (MgSO4) and the solvent evaporated to provide the title compound as the free base.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[C:4]=1[CH:5]=[O:6])[CH3:2].B.C1COCC1.Cl.CCOCC>C1COCC1>[CH2:1]([C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[C:4]=1[CH2:5][OH:6])[CH3:2]
Reactant: CCc1cccc(CC)c1C=O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1cccc(CC)c1CO
Temperature: 0 °C
Yield: 97.4 %

Procedure:
To a solution of 2,6-diethyl-benzaldehyde (0.68 g; 4.19 mmol) in THF (15 mL) was added dropwise a solution of BH3.THF in THF (8.38 ml; 1.00 mol/l; 8.38 mmol), at 0° C. After complete addition the mixture was heated under reflux for 3 hours. Subsequently, the resulting mixture was cooled to 0° C. and 1M aqueous HCl (10 ml) was added dropwise. The mixture was allowed to warm to room temperature (˜10 min.), and treated with Et2O. The layers were separated, the organic layer washed with 1M aqueous HCl (2×), 5% aqueous NaHCO3 (2×), and brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford (2,6-diethyl-phenyl)-methanol (0.67 g), which was used as such.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17](C=O)([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:24])[N:3]1[CH2:25][CH2:26][CH3:27].CC1C([P+]([O:48][C:49]([CH3:51])=[O:50])(C2C=CC=CC=2)C2C=CC=CC=2)=CC=CC=1.O1CCC[CH2:53]1>>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:15][CH2:16][C:17]([CH:53]=[CH:51][C:49]([OH:48])=[O:50])([CH2:20][CH2:21]3)[CH2:18][CH2:19]4)[NH:6][C:5]=2[C:4](=[O:24])[N:3]1[CH2:25][CH2:26][CH3:27]
Reactant: C1CCOC1
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C=O)(CC3)CC4)nc2n(CCC)c1=O
Reactant: CC(=O)O[P+](c1ccccc1)(c1ccccc1)c1ccccc1C
Product: CCCn1c(=O)c2[nH]c(C34CCC(C=CC(=O)O)(CC3)CC4)nc2n(CCC)c1=O

Procedure:
4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde (XI, Example 97b, 0.300 kg) and tetrahydrofuran (4.95 l) are mixed under an atmosphere of nitrogen and methyl(triphenylphosphoranylidene) acetate (0.555 kg) is added. The reaction mixture is heated to 65 to 75° and the reaction mixture stirred at this temperature until the starting aldehyde is consumed (17 hours). The mixture is cooled to 35 to 40° and a mixture of sodium hydroxide (0.132 kg) in water (4.95 l) is added. The mixture is heated to reflux and stirred until the hydrolysis of the ester is complete (3 hours). The reaction mixture is cooled to 35 to 40° and the organic solvent removed in vacuo at 40 to 45°. Ethyl acetate (3.00 l) and water (1.80 l) are added to the aqueous residue and the mixture is vigorously stirred for 15 mins. The layers are separated and the aqueous layer is washed with ethyl acetate (2×3.00 l). The aqueous layer is filtered, the filtrate is cooled to 0 to 5° and acidified to pH=1 with concentrated hydrochloric acid (0.270 l). The mixture is stirred at 0 to 5° for 1 hour. The resultant slurry is filtered and the filter pad washed with water (0.300 l). The solid is dried in vacuo at 45 to 55° for 24 hours to the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[NH2:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[N:26][NH:27]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:15][CH2:16][CH3:17])[N:5]=[CH:4][C:3]([C:18]#[N:19])=[C:2]2[NH:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[N:26][NH:27]2)=[CH:23][CH:22]=1)[CH3:14]
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4cn[nH]c4c3)c2cc1OCC
Temperature: 100 °C
Yield: 83 %

Procedure:
A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 250 mg (1.88 mM) of 6-aminoindazole in 10 ml of ethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80° C. to yield 448 mg of 6,7-Diethoxy-4-(1H-indazol-6-ylamino)-quinoline-3-carbonitrile as a tan solid: mass spectrum (electrospray, m/e): M+H 374.1, mp=143-145° C.
Reaction SMILES: C1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[N:12][N:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:10](=[O:18])[C:9]=1[OH:19].C(=O)[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[C:14]([N:11]1[C:10](=[O:18])[CH:9]([OH:19])[C:8](=[N:7][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:13]=[N:12]1)([CH3:16])([CH3:15])[CH3:17]
Reactant: O=Cc1ccncc1
Reactant: CC(C)(C)n1ncc(N)c(O)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)N1N=CC(=Nc2ccncc2)C(O)C1=O
Yield: 74.9 %

Procedure:
50 ml of a dry benzene solution of 3.1 g of 5-amino-2-tert-butyl-4-hydroxypyridazin-3-(2H)-one, 1.9 g of isonicotinaldehyde and 0.17 g of p-toluene sulfonic acid, was reacted for 1.5 hours under heating and refluxing by means of a Dean Stark trap. After cooling, 100 ml of ethyl acetate was added to the reaction mixture, and the mixture was washed with water and then with a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 3.3 g of 2-tert-butyl-4-hydroxy-5-(4-pyridylimino)pyridazin-3-(2H)-one as a powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:9]=2[CH2:18][CH2:19][NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:5]=[CH:4][N:3]=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CN1CCCC1=O>[N:35]1([C:2]2[CH:7]=[C:6]([C:8]3[NH:12][N:11]=[C:10]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[C:9]=3[CH2:18][CH2:19][NH:20][S:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:28][CH:29]=3)(=[O:23])=[O:22])[CH:5]=[CH:4][N:3]=2)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: CCCCCc1ccc(S(=O)(=O)NCCc2c(-c3cccs3)n[nH]c2-c2ccnc(Cl)c2)cc1
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Product: CCCCCc1ccc(S(=O)(=O)NCCc2c(-c3cccs3)n[nH]c2-c2ccnc(N3CCOCC3)c2)cc1
Temperature: 190 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
A mixture of N- {2-[5-(2-Chloro-pyridin-4-yl)-3-thiophen-2-yl-1H-pyrazol-4-yl]-ethyl}-4-pentyl-benzenesulfonamide (10 mg, 19.4 μmol) and morpholine (17 μl, 194 μmol) in 1-methyl-2-pyrrolidinone (500 μL) was stirred at 190° C. in a seal tube for 3 h. The reaction mixture was concentrated to 2 ml. The crude product was purified by Prep-HPLC. Removal of the solvent in vacuo provided the title compound (8.3 mg, 76% yield). MS m/e 566; HPLC retention time 3.35 min (Method A).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:35])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23](Br)[N:24]=3)[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].[CH3:36][N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([Sn](CCCC)(CCCC)CCCC)=[N:38]1>CN(C=O)C.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.[Cu]I>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:35])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:39]4[C:40]5[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=5)[N:37]([CH3:36])[N:38]=4)[N:24]=3)[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)cn3COCC[Si](C)(C)C)c2ccccc21
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 125.1 %

Procedure:
In a dry round-bottomed flask 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (0.12 g, 0.21 mmol) and 1-methyl-3-tributylstannanyl-1H-indazole (117 mg, 0.28 mmol) were dissolved in DMF (2 ml). The reaction mixture was evacuated and backfilled with Argon then tetrakis(triphenylphosphine)palladium(0) (13 mg, 0.011 mmol) and copper(I) iodide (9 mg, 0.047 mmol) were added. The reaction mixture was stirred at 80° C. for 1.5 h then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over silica gel with MeOH/CH2Cl2 (0.5% NH4OH) (gradient 0-3% MeOH) to afford 161 mg of 2-(1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][NH:14][C:13]1=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][O-].[Na+].Cl[O-]>ClCCl.O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][N:14]([Cl:17])[C:13]1=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(N[C@H]1CN(Cl)C1=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of (S)-3-benzyloxycarbonylamino-2-azetidinone (440 mg) in dichloromethane (15 ml) was combined with a solution of borax (1.53 g) in water (10 ml) and cooled in an ice-bath to 0°-5° C. While stirring vigorously, a 5.07% solution of sodium hypochlorite (3.2 ml) was added; after 1 hour another portion (1.6 ml) of hypochlorite solutionwas added and stirring was continued for 1 hour at 0°-5° C. The organic layer was separated and the aqueous solution was extracted with dichloromethane. The combined extracts were dried (sodium sulfate) and solvent was removed in vacuo giving (S)-3-benzyloxycarbonylamino-1-chloroazetidin-2-one as an oil.
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].C(Cl)(=O)C([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@@H:4]1[C@H:6]([C:7]([Cl:19])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Temperature: 80 °C
Yield: 78.5 %

Procedure:
A stirred solution of 10.0 g (0.04 mole) of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid in 100 mL of toluene was heated to 80° C. To this solution at 80° C. was added dropwise over 10 minutes a solution of 10.5 g (0.08 mole) of oxalyl chloride in 5 mL of toluene, and the whole heated at 80° C. for 26 hours. The toluene and excess oxalyl chloride were removed by distillation to give a residual oil which was distilled under reduced pressure using a Kugelrohr distilling system to give 8.2 g of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride; b.p. 85° C./0.09 mm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.N[C:19]1([CH3:22])C[CH2:20]1.[CH2:23]([N:25](C(C)C)C(C)C)C>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:25][CH2:23][CH:22]2[CH2:19][CH2:20]2)[N:3]=1
Reactant: CC1(N)CC1
Reactant: CCN(C(C)C)C(C)C
Reactant: CS(=O)(=O)c1nc(Cl)c(C#N)c(NCCO)n1
Solvent: C1COCCO1
Product: N#Cc1c(Cl)nc(NCC2CC2)nc1NCCO

Procedure:
In analogy to the procedure described in example 47a, the crude 4-chloro-6-(2-hydroxy-ethylamino)-2-methanesulfonyl-pyrimidine-5-carbonitrile was treated with amino-methyl-cyclopropane in dioxane in the presence of N-ethyl-diisopropylamine at 40° C. to yield 4-chloro-2-(cyclopropylmethyl-amino)-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=268.
Reaction SMILES: [C:1](O)(=O)C.N[C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][N:7]=1.C=O.[BH3-][C:16]#[N:17].[Na+].[OH-].[Na+]>CC#N.O>[Cl:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([N:17]([CH3:16])[CH3:1])[CH:11]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CN(C)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.3 %

Procedure:
Acetic acid (0.6 ml, 10.5 mmol) was added dropwise to a solution of 2-amino-4-chloropyridine (384 mg, 3.0 mmol), formaldehyde (2.4 ml of a 37% aqueous solution, 29.6 mmol) and NaBH3CN (581 mg, 9.0 mmol) in MeCN (10 ml) and water (2 ml) at 0° C. After 10 minutes the reaction was warmed to room temperature and stirred for 3 days. The reaction was basified to pH4 with 1M aq. NaOH and then extracted with diethyl ether (3×30 ml), dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified by FCC (Hexane/Diethyl ether with gradient, 98:2 to 8:2) to provide the title compound as colourless oil (260 mg, 56%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([C:11]([F:14])([F:13])[F:12])=[N:4]1)C.ClC1[N:21]=[C:20]([NH2:22])[C:19]([F:23])=[CH:18][N:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].O.CN1C(=O)C[CH2:34][CH2:33]1>>[NH2:22][C:20]1[C:19]([F:23])=[CH:18][N:17]=[C:1]([N:3]2[CH:7]=[C:6]([C:8]([O:10][CH2:33][CH3:34])=[O:9])[C:5]([C:11]([F:14])([F:13])[F:12])=[N:4]2)[N:21]=1
Reactant: Nc1nc(Cl)ncc1F
Reactant: CN1CCCC1=O
Reactant: CCn1cc(C(=O)O)c(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CCOC(=O)c1cn(-c2ncc(F)c(N)n2)nc1C(F)(F)F

Procedure:
A solution of ethyl 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (150 mg, 0.72 mmol), 2-chloro-5-fluoro-pyrimidin-4-ylamine (102 mg, 0.79 mmol) and Cs2CO3 (325 mg, 1 mmol) in NMP (1.0 mL) is heated in a microwave reactor at 150° C. for 1 h. The mixture is poured into H2O. The crude product is filtered out, dissolved in 10% MeOH in DCM, and dried over anhydrous Na2SO4. The title compound is purified by PTLC (eluted with 5% MeOH in DCM).