Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21]([F:23])[C:19]([NH2:20])=[N:18][C:16]1=[O:17])(=[O:3])[CH3:2].Cl[C:25]([O:27][CH2:28][CH2:29][CH:30]([CH3:47])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:46])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])=[O:26].CO>C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21]([F:23])[C:19]([NH:20][C:25]([O:27][CH2:28][CH2:29][CH:30]([CH3:47])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:46])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])=[O:26])=[N:18][C:16]1=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(F)c(N)nc1=O
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(F)c(NC(=O)OCCC(C)CCCC(C)CCCC(C)CCCC(C)C)nc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To the ice-cooled solution containing 2′,3′-Di-O-acetyl-5′-deoxy-5-fluoroocytidine (5) (9.76 g, 29.64 mmol) in dry CH2Cl2 (40 ml) and anhydrous pyridine (5 ml), phytanyl chloroformate (12 g, 33 mmol) (6a) was added dropwise in order to keep the low reaction temperature. After stirring the mixture for overnight at room temperature, MeOH (1.3 ml) was added in one portion to stop the reaction. The mixture was evaporated to a syrup mass under reduced pressure. To this residue, diethyl ether (50 ml) was added and the suspension was stirred for 30 min at room temperature. The insoluble precipitate was filtered through a glass filter. The precipitate was washed with 30 ml of diethyl ether. The filtrate and the washings were collected, dried over anhydrous Na2SO4, and evaporated to dryness. The crude target compound was further purified using silica column chromatography CH2Cl2:MeOH=5:1 to give 2′,3′-Di-O-acetyl-5′-deoxy-5-fluoro-N4-(phytanyloxycarbonyl)cytidine (16.7 g, 84.1%) (7a). 1H NMR in CDCl3: δ0.83, 0.85, 0.86, 0.88 (4s, each 3H, CH3), 0.91 (d, 3H, J=6.6 Hz, CH3), 0.96-1.88 (m, 24H, CH2+CH), 1.47 (d, 3H, J=6.6 Hz, H-5), 2.10, 2.12 (2s, each 3H, OMe), 4.13-4.37 (m, 3H, H-4+CH2OC═ONH), 5.01 (t, 1H, J=5.4 Hz, H-2), 5.29 (t, 1H, J=5.8 Hz, H-3), 5.96 (d, 1H, J=3.8 Hz, H-1), 7.39 (br s, 1H, N—CH═C—F).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Li+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O>CN(C=O)C>[O:13]=[C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][CH2:11][N:10]1[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1NCCN1Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To a solution of 1-benzylimidazolidin-2-one (3.5 g, 19.9 mmol) in DMF (50 ml) at 0° C. were added lithium tert-butoxide (1.9 g, 23.8 mmol) and tert-butyl bromoacetate (3.2 ml, 21.8 mmol). After stirring the mixture at room temperature overnight, the reaction mixture was poured into water (100 ml) and the mixture was extracted with ethyl acetate. The organic phase was washed with water, 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The organic solution was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crystalline residue was washed with n-hexane, and dried to give tert-butyl 2-(2-oxo-3-benzylimidazolidinyl)acetate (5.08 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=O)[CH:10]([CH2:16][C:17]([NH2:19])=[O:18])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].C([NH:23]C1C2C=CC=CC=2C2C(CC(=O)NN=2)C1)(=O)C>>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:11]3[CH:10]([CH2:16][C:17](=[O:18])[NH:19][N:23]=3)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CC2CC(=O)NN=C2c2ccccc21
Reactant: CC(=O)Nc1ccc2c(c1)CCC(CC(N)=O)C2=O
Product: CC(=O)Nc1ccc2c(c1)CCC1CC(=O)NN=C21

Procedure:
In a manner similar to that described in Preparation 1(d), 6-acetamido-1-oxo-1,2,3,4-tetrahydro-2-naphthylacetamide (1.55 g) was converted into 6-acetamido4,4a,5,6-tetrahydrobenzo[h]cinnolin-3[2H]-one (0.2 g; mp 259°); ν(Nujol mull) 3330, 3215, 1655, 1610cm-1 ; M+ =257.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[H-].[Na+].I[CH:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][N:8]([CH:18]([CH3:20])[CH3:19])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Cl)cc2[nH]ncc12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [H-]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
Methyl 6-chloro-1H-indazole-4-carboxylate (0.410 g, 1.947 mmol) was dissolved in DMF (10 mL) and placed into an ice bath and stirred for 15 min. Sodium hydride (0.101 g, 2.53 mmol) was added, the contents stirred for 15 min., and then 2-iodopropane (0.389 mL, 3.89 mmol) was added. The contents were stirred with warming to RT. After stirring at RT for 2 h, a scoop of sodium carbonate and then 0.4 mL of methyl iodide were added. After stirring at RT for an additional 1 h, the reaction mixture was diluted with saturated NH4Cl and then extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was dissolved in a minimal amount of DCM and purified by silica gel chromatography (eluent: 3-20% ethyl acetate in hexanes). The title compound was the less polar of the two products separated from chromatography, and was collected as 0.22 g (45% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45-1.52 (m, 6H), 3.93-3.99 (m, 3H), 5.11 (quin, J=6.57 Hz, 1H), 7.73 (d, J=1.77 Hz, 1H), 8.30 (s, 1H), 8.42 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[C:6](Cl)=[N:7][C:8]([Cl:12])=[N:9][C:10]=1[CH3:11])[CH2:2][CH2:3][CH3:4].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.O.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>[CH2:1]([C:5]1[C:10]([CH3:11])=[N:9][C:8]([Cl:12])=[N:7][C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OB(O)c1ccccc1
Reactant: CCCCc1c(C)nc(Cl)nc1Cl
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCc1c(C)nc(Cl)nc1-c1ccccc1
Reaction time: 6 h

Procedure:
A mixture of 5-butyl-2,4-dichloro-6-methyl-pyrimidine (711 mg, 3.24 mmol), phenylboronic acid (475 mg, 3.89 mmol), Na2CO3 (1.03 g, 9.73 mmol), and Pd(PPh3)4 (187 mg, 0.162 mmol) in toluene-EtOH—H2O (4 ml-0.5 ml-2 mL) is stirred at relux for 6 hours. After cooling, the reaction mixture is diluted with H2O and extracted with EtOAc. The extract is then washed with brine, dried over Na2SO4, and concentrated. The residue is purified by flash chromatography on silica gel. Elution with 8:1 hexanes-EtOAc followed by 7:1 hexanes-EtOAc affords 5-butyl-2-chloro-4-methyl-6-phenyl-pyrimidine as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.45 (m, 5H), 2.65–2.62 (m, 2H), 2.60 (s, 3H), 1.46–1.36 (m, 2H), 1.25 (sext, J=7.2 Hz, 2H), 0.81 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][N:28]([C:8]([CH:5]4[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:7][CH2:6]4)=[O:10])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: CC1CCC(C(=O)O)CC1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: CC1CCC(C(=O)N2CCN(c3ccc(C(=O)NCCC4CC4)nn3)CC2)CC1

Procedure:
Following the procedure of Example 14, making variations only as required to use 4-methylcyclohexanecarboxylic acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (43% yield). 1H NMR (300 MHz, CDCl3) δ 8.07, 7.09, 7.05, 3.89, 3.79, 3.64-3.70, 3.56, 2.40-2.60, 1.65-1.88, 1.50-1.62, 0.99, 0.91, 0.75, 0.48, 0.10. MS (ES+) m/z 400 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]([O-])=[O:20])[S:18][C:11]=12.[Li+]>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:19]([C:17]1[S:18][C:11]2[C:12](=[N:13][CH:14]=[CH:15][C:10]=2[Cl:9])[CH:16]=1)=[O:20]
Reactant: NCc1ccccn1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: O=C(NCc1ccccn1)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 2-aminomethylpyridine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 304/306 (MH+); HPLC Rf: 4.36 min.; HPLC purity: 97%.
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[N:10]=[C:11](Cl)[C:12]3[S:17][C:16]([NH2:18])=[N:15][C:13]=3[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][C:21]1([CH2:26][OH:27])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[NH2:18][C:16]1[S:17][C:12]2[C:11]([NH:20][C:21]3([CH2:26][OH:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:10][C:9]([S:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:14][C:13]=2[N:15]=1
Reactant: NC1(CO)CCCC1
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Product: Nc1nc2nc(SCc3ccccc3)nc(NC3(CO)CCCC3)c2s1

Procedure:
Prepared according to the procedure in Example 1, from 5-phenylmethylthio-7-chloro-thiazolo[4,5-d]pyrimidin-2-ylamine and cycloleucinol.
Reaction SMILES: [H-].[Na+].[C:3]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:16]([O:27]C(C)(C)C)(=[O:26])[CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].Cl>O>[C:3]1([CH:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][C:16]([OH:27])=[O:26])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)CCC(=O)OC(C)(C)C
Reactant: O=C1CCCCCCCCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)C(CC(=O)O)C1=CCCCCCCCCCC1
Yield: 100 %

Procedure:
20.06 Grams (0.418 mole) of 50% sodium hydride dispersion was introduced into a 1 liter four-necked flask equipped with a thermometer, a tap funnel, a reflux cooler and a stirrer and washed with benzene. Then 500 ml of pure tetrahydrofuran and 20 ml of t-BuOH were added thereto and the mixture was refluxed for 30 mins. During the reflux, there was dropwise added 150 ml of pure tetrahydrofuran containing dissolved therein 61.87 g (0.340 mol) of cyclododecanone and 86.0 g (0.374 mol) of di-tert-butyl succinate, over 1.5 hour. After that the reflux was continued to complete the reaction. After the reaction, a mixture of 100 ml of water and 78 ml of concentrated hydrochloric acid was added to the reaction product and the obtained mixture was concentrated. The solvent was removed and the product mixture was twice extracted with 250 ml of ether. The extract liquid was washed with water and dried, followed by concentration to obtain 115.1 g of crude β-cyclododecenyl-β-tert-butoxycarbonyl propionic acid II with the purity of 86.8% and the yield of 86.9%. The crude product was found to include about 2% of cyclododecanone and about 5% of high boiling point-having by-products and the balance of the impurities was solvents.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Sn](CCCC)(CCCC)CCCC)[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([S:38]([C:41]1[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=1)(=[O:40])=[O:39])[CH:33]=[C:32]2I>CN(C=O)C.[Cu]I.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>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([S:38]([C:41]1[CH:42]=[CH:43][C:44]([CH3:45])=[CH:46][CH:47]=1)(=[O:39])=[O:40])[CH:33]=[C:32]2[C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4c(F)cccc4Cl)ccc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(Cl)n1
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: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(Cl)n3)c3cc(-c4c(F)cccc4Cl)ccc32)cc1
Temperature: 105 °C
Yield: 90.4 %

Procedure:
Argon was bubbled through a slurry of CuI (0.036 g, 0.190 mmol), Pd(PPh3)4 (0.110 g, 0.095 mmol), 2-chloro-6-(tributylstannyl)pyrazine (1.151 g, 2.85 mmol), 5-(2-chloro-6-fluorophenyl)-3-iodo-1-tosyl-1H-indole (1.00 g, 1.902 mmol) in 9 mL DMF for 2 min. The reaction was sealed and heated to 105° C. for 2 h. The reaction was cooled and partitioned between EtOAc and water. The organic layer was washed 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (80 g column) using 0-30% EtOAc/hexane. The product-containing fractions were concentrated to afford 5-(2-chloro-6-fluorophenyl)-3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indole (0.88 g, 1.72 mmol, 91% yield) as a light-yellow solid. MS (ESI, pos. ion) m/z: 512 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=2)[CH2:16]1.[CH3:39][O:40][CH2:41][C:42](Cl)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:5][N:6]([CH2:42][CH2:41][O:40][CH3:39])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=2)[CH2:16]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Reactant: COCC(=O)Cl
Product: COCCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (450 mg) and methoxyacetyl chloride (0.48 ml) according to an analogous synthetic method to Example 152, the title compound (400 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)[N:6]=1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([CH:12]2[CH2:16][CH2:15][O:14][CH2:13]2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(-c2ccoc2)cnc1N
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1nc(C2CCOC2)cnc1N
Reaction time: 40 h

Procedure:
A solution of 3-amino-6-(furan-3-yl)-pyrazine-2-carboxylic acid methyl ester (2.9 g, 13.2 mmol) in MeOH (150 ml) was treated with palladium on carbon (10%; 0.6 g, 0.28 mmol) and hydrogenated at 1.2 atmospheres for 40 h. Another 2 equivalents of palladium on carbon were consecutively added and the hydrogenation was continued for another 72 h. The reaction mixture was filtered and the catalyst was washed with MeOH. The solution was concentrated in vacuo and the product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as light yellow solid (0.3 g, 10%).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[N:13](C)[C:14](=O)C(F)(F)F.[OH-].[Na+].Cl>C1COCC1>[CH3:14][NH:13][C:5]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:21])=[O:2]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N(C)C(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNc1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
A mixture of 2-[methyl-(2,2,2-trifluoro-acetyl)-amino]-3-nitro-benzoic acid methyl ester (1.7 g, 5.5 mmol) and 5 M aqueous NaOH (5 mL) in THF (10 mL) was stirred at 50° C. for several hours. The mixture was acidified with 4 M HCl and extracted with EtOAc to provide 2-methylamino-3-nitro-benzoic acid. MS m/z: 197.0 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([OH:24])=O)=[N:20][CH:21]=3)[N:12]=2)[CH:8]=[CH:7][C:6]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].C(Cl)(=O)C(Cl)=O.[NH3:38].O1CCOCC1>C(Cl)Cl.CN(C=O)C>[CH3:2][O:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([NH2:38])=[O:24])=[N:20][CH:21]=3)[N:12]=2)[CH:8]=[CH:7][C:6]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)O)nc3)no2)ccc1-c1ccccc1C
Reactant: N
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COCc1cc(-c2nc(-c3ccc(C(N)=O)nc3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of 5-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}pyridine-2-carboxylic acid hydrochloride (100 mg, 0.23 mmol) in anhydrous DCM (5 mL) was added oxalyl chloride (0.058 mL, 0.69 mmol) and DMF (1 drop). The resulting mixture was stirred at RT for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was taken up with anhydrous THF (2 mL) and a 0.5N solution of ammonia in dioxane (4.5 mL, 2.25 mmol) was added. The mixture was stirred at RT for 1 hour, and then concentrated under reduced pressure. The residue was taken up with Et2O. The precipitate was filtered off, washed with Et2O and dried under reduced pressure to give the title compound as a beige powder (88 mg, 96%). HPLC (Method A), Rt: 4.7 min (purity: 95.4%). UPLC/MS, M+(ESI): 401.2. 1H NMR (CD3OD, 300 MHz) δ 9.41 (dd, J=2.1, 0.9 Hz, 1H), 8.71 (dd, J=8.2, 2.1 Hz, 1H), 8.44 (d, J=1.8 Hz, 1H), 8.31 (dd, J=8.2, 0.9 Hz, 1H), 8.24 (dd, J=7.9, 1.8 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 7.34 (m, 2H), 7.28 (m, 1H), 7.13 (d, J=7.1 Hz, 1H), 4.24 (s, 2H), 3.32 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([CH3:14])[CH2:10][SiH:11]([Cl:13])[Cl:12].[CH2:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:13][Si:11]([Cl:12])([CH2:10][CH:9]([C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:14])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=Cc1ccccc1
Reactant: Cc1ccc(C)c(C(C)C[SiH](Cl)Cl)c1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: Cc1ccc(C)c(C(C)C[Si](Cl)(Cl)CCc2ccccc2)c1
Yield: 78 %

Procedure:
In the same apparatus and procedure as EXAMPLE 1, 6.2 g (0.027 mole) of 3-(2,5-dimethylphenyl)-1,1-dichloro-1-silabutane, 5.4 g (0.05 mole) of styrene, and 90 μl of 1% chloroplatinic acid in isopropanol were placed and refluxed under the dry nitrogen atmosphere for 3 hours. Vacuum distillation of the reaction products gave 7.4 g (bp, 139°-141° C./0.6 mmHg) of 3,3-dichloro-5-(2,5-dimethylphenyl)-1-phenyl-3-silahexane.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)(=[O:4])=[O:3].C(OCC)(=O)C>CO.[Pd]>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH2:12])=[N:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C#N)nc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(CN)nc1

Procedure:
A solution of 5-methanesulfonyl-pyridine-2-carbonitrile (120 mg, 0.66 mmol) in methanol was hydrogenated over 10% Pd/C catalyst using a continuous flow hydrogenation apparatus (conditions: flow rate 1 mL/minute, 10 bars, 25° C.). The reaction was monitored by HPLC-MS and TLC (ethyl acetate) indicating the disappearance of starting material. The mixture was concentrated in vacuo and then twice diluted with ether-hexanes and concentrated to afford the title compound.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([C:14]2[N:18]([CH2:19][CH3:20])[C:17]([CH3:21])=[N:16][C:15]=2[CH3:22])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([Li])CCC.CCCCCC.IC>C1COCC1.O>[NH:1]([C:8]1[N:13]=[C:12]([C:14]2[N:18]([CH2:19][CH3:20])[C:17]([CH2:21][CH3:23])=[N:16][C:15]=2[CH3:22])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1c(C)nc(C)c1-c1ccnc(Nc2ccccc2)n1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: CCc1nc(C)c(-c2ccnc(Nc3ccccc3)n2)n1CC
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 13 %

Procedure:
2-Anilino4-(l-ethyl-2,4dimethylimidazol-5-yl)pyrimidine (Method 11; 200 mg, 0.68 mmol) was dissolved in anhydrous THF (10 ml) under an inert atmosphere. The stirring solution was cooled using dry-ice/acetone bath to −70° C. A 1.6 M solution of n-butyl lithium in hexane (900 μl, 1.44 mmol) was added drop-wise keeping temperature <−60° C. until the dark red colour remained. At this point 1.6 M n-butyl lithium in hexane (450 μl, 0.72 mmol) was added and the solution stirred at −70° C. for 10 minutes. Iodomethane (99 μl, 1.50 mmol) was added, the temperature was maintained at −70° C. for an additional 10 minutes then allowed to rise to room temperature. The reaction was allowed to stir for 1 hr at room temperature when water (100 ml) was added. The aqueous layer extracted with EtOAc (2×20 ml). Organics were combined, dried solvent evaporated in vacuo. The residue was purified by flash silica chromatography DCM:MeOH (increasing in polarity from 100:0 to 96:4) to yield the title compound (28 mg, 13%). M/z 322.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:3][CH2:2]1.[N:19]1([C:25]2[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:25]3[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=3)[CH2:20][CH2:21]2)=[O:10])[CH2:2][CH2:3]1
Reactant: N#Cc1cnc(N2CCNCC2)s1
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)N2CCN(c3ncc(C#N)s3)CC2)c1
Yield: 75 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (Example A5) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 75%). MS (m/e): 447.3 (M+H+, 100%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1.[F:14][C:15]([F:30])([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2)[C:16]([NH:18][NH2:19])=O.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>C(O)CCC>[F:30][C:15]([F:14])([C:16]1[N:3]2[N:4]=[C:5]([C:8]3[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=3)[CH:6]=[CH:7][C:2]2=[N:19][N:18]=1)[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2
Reactant: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cn1cc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)cn1
Temperature: 130 °C
Yield: 61.8 %

Procedure:
A mixture of 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-pyridazine (step d) (4.57 g, 23.6 mmol) and difluoro-quinolin-6-yl-acetic acid hydrazide (step c) (5.60 g, 23.6 mmol) in n-butanol (125 mL) was heated to 130° C. overnight. The mixture was cooled to room temperature, followed by aqueous work up using AcOEt and a solution of K2CO3. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography (first chromatography: CH2Cl2 100% and CH2Cl2/MeOH: 88/12 followed by another column with toluene/iPrOH/NH4OH: 85/15/2) to give the title compound (5.5 g, 62%). M.p=199.7° C.