Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(COC([NH:11][C@@H:12]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:13]([OH:34])[CH2:14][NH:15][C@H:16]([C:24]([O:26]CC2C=CC=CC=2)=[O:25])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=O)C=CC=CC=1.[ClH:42]>C(O)C.[Pd]>[ClH:42].[ClH:42].[NH2:11][C@@H:12]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:13]([OH:34])[CH2:14][NH:15][C@H:16]([C:24]([OH:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(O)CN[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N[C@@H](Cc1ccccc1)C(O)CN[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of N-[(3S)-3-[[(Phenylmethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]-L-phenylalanine, phenylmethyl ester (1.14 g, 2.06 mmol) in 30 ml of 95% ethanol was added 4.2 ml of lN hydrogen chloride and 250 mg of 10% palladium on carbon catalyst. The reaction mixture was stirred at room temperature under an atmosphere of hydrogen. A white precipitate which separated upon addition of the aqueous hydrogen chloride redissolved as the reaction proceeded. After 17 hours, the catalyst was filtered and the solvent was evaporated. Trituration with methanolether afforded 531 mg of the title compound as a white solid, melting point 147-163° C. The 1H-NMR showed an approximately 1:1 mixture of alcohol isomers. Evaporation of the filtrate from the trituration gave 0.21 g of material which was enriched in one of the diastereomers.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:6][C:7]=1[CH3:8].C(O)CCC.[C:21]([NH:24][NH2:25])(=O)[CH3:22].[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl.CCCCCC>[Cl:15][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[C:7]([CH3:8])[C:2]3[N:3]([C:21]([CH3:22])=[N:24][N:25]=3)[N:4]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)NN
Reactant: Cc1cc(-c2cccc(Cl)c2)nnc1Cl
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: CCCCO
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1cc(-c2cccc(Cl)c2)nn2c(C)nnc12

Procedure:
A mixture of 7.17 g. of 3-chloro-6-(m-chlorophenyl)-4-methylpyridazine, 100 ml. of n-butanol and 6.96 g. of acetylhydrazine is refluxed overnight. The mixture is coated and filtered to give solid. The solid is dissolved in methylene chloride and the solution passed through a short column of hydrous magnesium silicate. The eluent is refluxed while hexane is gradually added until crystals separated. Cooling and filtering gives 3.30 g. of crystals, m.p. 193.5°-195.5° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.S(O[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)(C1C=CC(C)=CC=1)(=O)=O>CO>[N:1]1([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:26][CH2:27][CH:28]([NH:31][C:32]([O:34][CH2:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[O:33])[CH2:29][CH2:30]3)=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(N3CCC(NC(=O)OCc4ccccc4)CC3)cc2)cc1
Reactant: c1c[nH]nn1
Solvent: CO
Product: O=C(NC1CCN(c2ccc(CCn3ccnn3)cc2)CC1)OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
1,2,3-triazole (3.4 ml, 58.6 mmol) was added to the N-(4-(2-tosyloxyethyl)phenyl)-4-benzyloxycarbonylaminopiperidine (3.0 g, 5.90 mmol) obtained in Example 7(5), followed by stirring at 90° C. for 2 hours. Methanol was added to the reaction mixture. The mixture was refluxed under heat for 1 hour, and then allowed to cool to room temperature. The precipitate was collected by filtration, thereby obtaining N-(4-(2-(1,2,3-triazol-1-yl)-ethyl)-phenyl)-4-benzyloxycarbonylaminopiperidine (1.3 g, 54%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH2:10][NH:9][CH2:8]2)=[C:4]([F:13])[CH:3]=1.CCN(CC)CC.[Cl:21][C:22]1[N:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1>CC#N>[Cl:21][C:22]1[N:27]=[C:26]([N:9]2[CH2:10][CH:7]([O:6][C:5]3[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][C:4]=3[F:13])[CH2:8]2)[N:25]=[CH:24][N:23]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: Fc1cc(Cl)ccc1OC1CNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Fc1cc(Cl)ccc1OC1CN(c2ncnc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
To a solution of 3-(4-chloro-2-fluorophenoxy) azetidine (3.6 g, 18.0 mmol) in CH3CN (60 mL, 3 mL/mmol) was added Et3N (7.2 mL, 50.0 mmol) and 2, 4-dichloro-1, 3, 5-triazine (3.0 g, 20.0 mmol) and the reaction mixture was stirred at RT for 1 h. Then the reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×50 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography to obtain 2-chloro-4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)-1,3,5-triazine (0.800 g, 20%) as a solid. Observed mass (M+1): 315.0
Reaction SMILES: C(OC([N:8]([CH:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Br:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.C(OC([NH:37][C@H]1CCN(S(C2C3C(Cl)=CN=C(Cl)C=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:37][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][CH:10]([NH:8][CH3:9])[CH2:11]3)(=[O:17])=[O:16])[C:19]=2[C:20]([Br:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Br)c23)C1
Product: CNC1CCN(S(=O)(=O)c2cccc3c(N)ncc(Br)c23)C1
Product: Cl

Procedure:
Intermediate 24 can be used in the method of Example 39-1 instead of Intermediate 26a to obtain the title compound as hydrochloride.
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4])=[CH2:2].[C:16]1([S:22]Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)[Cl:25]>>[C:16]1([S:22][CH:1]([S:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=2)(=[O:5])=[O:4])[CH2:2][Cl:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClSc1ccccc1
Reactant: ClCCl
Reactant: C=CS(=O)(=O)c1ccc(C(C)(C)C)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)C(CCl)Sc2ccccc2)cc1
Reaction time: 1.25 h
Yield: 86 %

Procedure:
To a solution of 21.0 g (93.7 moles) of p-t-butylphenyl vinyl sulfone in 100 ml of methylene chloride at 20° C. was added 14.0 ml (17,5 g, 121 mmoles) of benzenesulfenyl chloride. After 75 minutes the initial red color of the solution had changed to orange. In the same time the temperature of the solution rose to 26° C. After three days at 23° C. the solvent was removed by evaporation. The semicrystalline residue was recrystallized from ethyl acetate-pentane (1:2) to give a first crop of 18.3 g (53%), m.p. 104.0°-105.5° C. and subsequent crops of 8.3 and 3.0 g, for a total yield of 86%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39](CO)[CH:38]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][C:39]2[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCc1cccnc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4cccnc4)c(C)c3C)c2cc1OC
Yield: 112.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-pyridylmethanol (25 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (80 mg, yield 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1)=[O:5].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+].O>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)ccc1Cl
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1ccc(-n2ccnc2)cc1)c1cc(Cl)ccc1Cl
Temperature: 110 °C
Yield: 87.3 %

Procedure:
A 2-L three-necked flask equipped with a stirrer, a thermometer, a condenser tube and a nitrogen inlet tube was charged with 150.7 g (0.560 mol) of 2,5-dichloro-4′-fluorobenzophenone, 114.4 g (1.68 mol) of imidazole, 100.6 g (0.728 mol) of potassium carbonate and 840 ml of N,N′-dimethylacetamide. The reaction solution was heated under a nitrogen atmosphere in an oil bath at 110° C. for 2 hours. After thin layer chromatography confirmed that the materials showed no peaks, the reaction liquid was allowed to cool to room temperature. The reaction liquid was slowly added to 3 L of water, and the product was precipitated. The liquid was then filtered. The product obtained by the filtration was dissolved in THF (1.2 L), and toluene (4 L) was added to the solution. The mixture was washed with salt solution until the water phase became neutral. The organic phase was dried over magnesium sulfate, and the solvent was evaporated with an evaporator. A crude product weighing 180 g was obtained. The crude product was subjected to recrystallization using 1 L of toluene and 20 ml of methanol in combination at 80° C., and the resultant crystal was isolated. As a result, 155 g of a white solid was obtained with a yield of 87%. A 1H-NMR spectrum of the compound is shown in FIG. 1.
Reaction SMILES: [Li+].[F:2][C:3]1[C:11]([O:12][C:13]2[C:14]3[CH:21]=[C:20]([C:22]4[CH:30]=[CH:29][C:25]([C:26]([O-:28])=O)=[CH:24][CH:23]=4)[NH:19][C:15]=3[N:16]=[CH:17][N:18]=2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:31])[NH:7]2.[CH2:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH3:33].C(OP(C#N)(=O)OCC)C>CN(C=O)C.CCOC(C)=O>[CH2:32]([N:34]1[CH2:39][CH2:38][N:37]([C:26]([C:25]2[CH:24]=[CH:23][C:22]([C:20]3[NH:19][C:15]4[N:16]=[CH:17][N:18]=[C:13]([O:12][C:11]5[C:3]([F:2])=[C:4]6[C:8](=[CH:9][CH:10]=5)[NH:7][C:6]([CH3:31])=[CH:5]6)[C:14]=4[CH:21]=3)=[CH:30][CH:29]=2)=[O:28])[CH2:36][CH2:35]1)[CH3:33]
Reactant: CCN1CCNCC1
Reactant: Cc1cc2c(F)c(Oc3ncnc4[nH]c(-c5ccc(C(=O)[O-])cc5)cc34)ccc2[nH]1
Agent: CCOP(=O)(C#N)OCC
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN1CCN(C(=O)c2ccc(-c3cc4c(Oc5ccc6[nH]c(C)cc6c5F)ncnc4[nH]3)cc2)CC1
Reaction time: 1 h

Procedure:
To 340 mg (0.83 mMol) 4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoic acid lithium salt in 5 ml of DMF under N2-atmosphere, 0.38 ml (3 mMol) of N-ethylpiperazine and 0.31 ml (95%; 2 mMol) of diethyl-cyanphosphonate are added at 0° C. After 60 min, the suspension is diluted with EtOAc and washed with saturated NaHCO3-solution, water and brine. The aqueous layers are reextracted twice with EtOAc, the organic layers dried (Na2SO4) and concentrated after adding SiO2. The resulting powder is put on top of a chromatography column (SiO2) and the title compound eluted with EtOAc/methanol/NH3conc. 80:20:1; HPLC (conditions see Examples 67-78) tR=10.4 min; MS-ES+: (M+H)+=499.
Reaction SMILES: Br[C:2]1[C:3]([CH3:20])=[N:4][N:5]2[C:10]3[N:11]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:12][CH2:13][C:9]=3[C:8]([CH3:19])=[N:7][C:6]=12.[O:21]1[C:25]([Sn](CCCC)(CCCC)CCCC)=[CH:24][C:23]2[CH:39]=[CH:40][CH:41]=[CH:42][C:22]1=2.C(OCC)(=O)C.O>CN(C)C=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>[O:21]1[C:25]([C:2]2[C:3]([CH3:20])=[N:4][N:5]3[C:10]4[N:11]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:12][CH2:13][C:9]=4[C:8]([CH3:19])=[N:7][C:6]=23)=[CH:24][C:23]2[CH:39]=[CH:40][CH:41]=[CH:42][C:22]1=2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2ccccc2o1
Reactant: CCC(CC)N1CCc2c(C)nc3c(Br)c(C)nn3c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)N1CCc2c(C)nc3c(-c4cc5ccccc5o4)c(C)nn3c21
Yield: 33.3 %

Procedure:
A solution of 3-bromo-8-(1-ethylpropyl)-2,5-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (300 mg, 0.89 mmol), benzo[b]furan-2-yl(tributyl)tin (0.72 g, 1.78 mmol) and Pd(PPh3)4 (103 mg, 0.90 mmol) in N,N-dimethylformamide (15 mL) was stirred at 120° C. for one day. Ethyl acetate and water were added thereto, followed by filtering through Celite. The organic layer of the filtrate was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (0-5% ethyl acetate/hexane), to give the title compound (111 mg) as white crystals.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:16])([F:15])[C:5]1[CH:6]=[N:7][C:8]2[CH2:9][CH2:10][NH:11][CH2:12][C:13]=2[CH:14]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:29][CH2:28][C@:27]([CH:33]([CH3:35])[CH3:34])([C:30](O)=[O:31])[CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:33]([C@:27]1([C:30]([N:11]2[CH2:10][CH2:9][C:8]3[N:7]=[CH:6][C:5]([C:4]([F:15])([F:3])[F:16])=[CH:14][C:13]=3[CH2:12]2)=[O:31])[CH2:28][CH2:29][C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:26]1)([CH3:35])[CH3:34]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@]1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.7 %

Procedure:
To a solution of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine dihydrochloride (159 mg, 0.574 mmol) of Step A-1, (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (0.21 g, 0.79 mmol) of Step A-4 in Example 1 in dichloromethane (10 mL) were added 4-dimethylaminopyridine (38 mg, 0.32 mmol) and diisopropylethylamine (180 mg, 1.4 mmol) followed by bromotris(pyrrolydino)phophonium hexafluorophosphate (270 mg, 0.57 mmol). After being stirred overnight at room temperature, the solution was diluted with dichloromethane, washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography on silica eluting with 30% ethyl acetate in hexanes to give 300 mg of desired product. MS calculated for C23H32F3N3O3: (M+H)+456; found 356.2 (M−Boc+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]2[CH2:8][C@@H:4]([C:5](=[O:18])[N:6]2[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:3]1.[H-].[Na+].[CH3:21]I>C1COCC1>[CH3:21][O:1][C@@H:2]1[C@@H:7]2[CH2:8][C@@H:4]([C:5](=[O:18])[N:6]2[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:3]1
Reactant: COc1ccc(CN2C(=O)[C@H]3C[C@H](O)[C@@H]2C3)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@H]3C[C@H](OC)[C@@H]2C3)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a solution of the (1S,4R,6S)-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]-heptan-3-one (500 mg, 2.02 mmol) in anhydrous THF (20 mL) was added NaH (60 wt %, 4.04 mmol) at room temperature. The mixture was stirred at 40° C. for 30 min. After cooling to room temperature, CH3I (0.41 mL, 8.08 mmol) was added. The reaction mixture was stirred for 1 h at ambient temperature and quenched with water (50 mL), extracted by EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and evaporated to give (1S,4R,6S)-6-methoxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one. MS (ESI+): m/z 262 (M+H+).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[C:21]1([C:27]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:28][CH2:29][CH:30]([OH:36])[CH2:31][C:32](OC)=[O:33])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.O>[C:21]1([C:27]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:28][CH2:29][CH:30]([OH:36])[CH2:31][C:32](=[O:33])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CC(C)(C)OC(=O)CC(=O)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
125 mL of THF and 24 g of diisopropylamine were charged and cooled to −15° C. 168 mL of 1.2 N n-BuLi was added at −15 to −5° C. and was stirred for 30 minutes. 21.56 g of tert-butyl acetate in 45 mL of THF, which was pre-cooled to −45° C., was added maintaining the temperature between −45 to −25° C. for 60 minutes. The reaction mixture was cooled to −45° C. and 30 g of methyl 4-triphenylmethyloxy-3-hydroxybutyrate in THF was added over a period of 20 minutes and the stirring was continued at −25° C. for 90 minutes. Water was added and the layers were separated. The aqueous layer was extracted using EtOAc and the combined organic layers were washed with brine, water, dried and concentrated to give the title compound which was used as such for the next step.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH3:25][C@H:26]([NH2:29])[CH2:27][OH:28]>>[OH:28][CH2:27][C@@H:26]([NH:29][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)[CH3:25]
Reactant: C[C@H](N)CO
Reactant: COC(=O)c1ccc(OCc2c(C3CCOCC3)noc2C)nc1
Product: Cc1onc(C2CCOCC2)c1COc1ccc(C(=O)N[C@@H](C)CO)cn1
Temperature: 50 °C
Yield: 22.2 %

Procedure:
A mixture of 6-[5-methyl-3-(tetrahydro-pyran-4-yl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.3 mol), S-(+)-2-amino-1-propanol (28.8 μL, 0.36 mmol) and TBD (12.8 mg, 0.09 mmol) was heated at 50° C. for 18 h under argon. The reaction mixture was concentrated onto silica then purified by chromatography (silica, 0 to 15% methanol in ethyl acetate) to give the title compound (30 mg, 27%) as a white solid. MS: m/e=374.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH2:12])=[O:10])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[CH2:24][C:25]1[N:29]2[N:30]=[C:31]([C:34](=O)[CH3:35])[CH:32]=[CH:33][C:28]2=[N:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:11]/[N:12]=[C:34](/[C:31]2[CH:32]=[CH:33][C:28]3[N:29]([C:25]([CH2:24][C:15]4[CH:16]=[C:17]5[C:22](=[CH:23][C:14]=4[F:13])[N:21]=[CH:20][CH:19]=[CH:18]5)=[CH:26][N:27]=3)[N:30]=2)\[CH3:35])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Reactant: NNC(=O)Nc1ccc(Cl)cc1
Product: C/C(=N\NC(=O)Nc1ccc(Cl)cc1)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1

Procedure:
The title compound was prepared from N-p-chlorophenylhydrazine carboxamide and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl-]ethanone in analogy to the synthesis of example 1. 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.20 (s, 1H), 9.18 (s, 1H), 8.86 (dd, 1H), 8.31 (m, 2H), 8.07 (d, 1H), 7.96 (d, 1H), 7.78 (d, 1H), 7.67 (m, 3H), 7.48 (q, 1H), 7.36 (d, 2H), 4.58 (s, 2H), 2.32 (s, 3H). LCMS (method C): [MH]+=489, tR=4.35 min.
Reaction SMILES: Cl[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.CS(C)=O.[CH2:15]([SH:17])[CH3:16].CC([O-])(C)C.[K+]>C1COCC1>[Cl:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([S:17][CH2:15][CH3:16])=[CH:7][CH:6]=1
Reactant: N#Cc1nc(Cl)ccc1Cl
Reactant: CCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCSc1ccc(Cl)nc1C#N
Temperature: 20 °C
Reaction time: 40 h
Yield: 31 %

Procedure:
In a reaction flask with condenser, mechanical stirrer, thermometer and dropping funnel were placed 53.4 g of 3,6-dichloro-2-pyridinecarbonitrile and 300 ml of DMSO. The mixture was chilled to about 10°-15° C. and then 19.8 g of ethanethiol was added. While maintaining the temperature at <20° C., 34.8 g of t-BuOK in 300 ml of THF was added in small portions. After the addition was complete, the reaction mixture was warmed to 20° C. and stirred for about 40 hrs. The reaction mixture was then poured onto about 2 kilograms (kg) of ice, stirred and filtered leaving a solid residue. The residue was washed with water, dissolved in CH2Cl2, dried over MgSO4, concentrated and diluted with hexane to give 19.0 g of 6-chloro-3-ethylthio-2-pyridinecarbonitrile. The filtrate was concentrated and separated on a Water's Prep LC 500 instrument using 15% ethyl acetate in hexane to give another 10.1 g of the same isomer. Total yield of 6-chloro-3-ethylthio-2-pyridinecarbonitrile was 29.1 g (46.5%), m.p. 79°-81° C. Further separation on the Prep LC 500 instrument gave a small amount of 3-chloro-6-ethylthio-2-pyridinecarbonitrile (m.p. 46°-48° C.) and 3,6-bis-ethylthio-2-pyridinecarbonitrile (m.p. 63°-64° C.).
Reaction SMILES: C([N:4]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:5]1[CH2:10][C:9]([CH:11]=O)=[N:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1=[O:20])(=O)C.N1C=CC=CC=1.Cl.[CH3:35][O:36][NH2:37]>CO>[C:24]([O:23][C:21]([NH:4][N:5]1[CH2:10][C:9](/[CH:11]=[N:37]/[O:36][CH3:35])=[N:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1=[O:20])=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(=O)N(C(=O)OC(C)(C)C)N1CC(C=O)=NN(C(=O)OC(C)(C)C)C1=O
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CO/N=C/C1=NN(C(=O)OC(C)(C)C)C(=O)N(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl 4-[acetyl(tert-butoxycarbonyl)amino]-6-formyl-3-oxo-5H-1,2,4-triazine-2-carboxylate (1.15 g, 3.00 mmol) in MeOH (1.8 mL) at room temperature was added pyridine (0.88 mL, 10.9 mmol) followed by O-methylhydroxylamine HCl salt (376 mg, 4.50 mmol). The obtained mixture was stirred for 20 h at room temperature and then concentrated under reduced pressure. The residual was redissolved in EtOAc, washed with water and dried (Na2SO4). After evaporation of the solvent, the crude product was obtained as a viscous oil which was used in the subsequent step without further purification. LCMS (Method I) RT 1.77 min. [M+H]+ 372.