Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:9]1[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[C:11]([C:18]([OH:20])=O)[CH:10]=1)=[O:8].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[F:44][C:45]([F:57])([F:56])[C:46]1[N:51]=[CH:50][C:49]([C@H:52]([NH2:55])[CH2:53][CH3:54])=[CH:48][CH:47]=1.C(N(CC)CC)C>CN(C)C=O>[F:56][C:45]([F:44])([F:57])[C:46]1[N:51]=[CH:50][C:49]([C@H:52]([NH:55][C:18]([C:11]2[CH:10]=[C:9]([C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[O:8])[N:17]3[CH2:16][CH2:15][O:14][CH2:13][C:12]=23)=[O:20])[CH2:53][CH3:54])=[CH:48][CH:47]=1
Reactant: CC[C@@H](N)c1ccc(C(F)(F)F)nc1
Reactant: C[C@H]1CCCN1C(=O)c1cc(C(=O)O)c2n1CCOC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C(F)(F)F)nc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (50 mg, 0.180 mmol) in dimethylformamide (2 ml) was added 1-hydroxybenzotriazole (27 mg, 0.197 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (38 mg, 0.197 mmol). The mixture was stirred for 90 min at 50° C., then (R)-1-(6-trifluoromethyl-pyridin-3-yl)-propylamine hydrochloride (48 mg, 0.20 mmol) and triethylamine (55 mg, 0.54 mmol) were added and the mixture was stirred at 25° C. overnight. The mixture was filtered through a small filter cartridge and the solution was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 45 mg (54%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propyl]-amide as white solid. LC/MS (method 5): Rt=4.12 min; m/z=465.35 (M+H+). 1H-NMR (400 MHz): δ (ppm)=8.76 (1H, s), 8.26 (1H, d), 8.01 (1H, d), 7.89 (1H, d), 7.24 (1H, s), 4.93-4.98 (2H, m), 4.84 (1H, d), 4.20-4.29 (2H, m), 3.92-3.99 (2H, m), 3.79-3.84 (1H, m), 3.69 (2H, bs), 2.07 (1H, m), 1.96 (1H, m), 1.77-1.89 (3H, m), 1.56 (1H, m), 1.19 (3H, d), 0.92 (3H, t).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:24])[C:6]1[CH:11]=[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[N:14]([CH3:20])[C:13]2=[O:21])[C:9]([F:22])=[CH:8][C:7]=1Cl)([CH3:3])[CH3:2].[Cu][C:26]#[N:27].C(OCC)(=O)C.Cl>CN1CCCN(C)C1=O.O>[CH:1]([O:4][C:5](=[O:24])[C:6]1[CH:11]=[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[N:14]([CH3:20])[C:13]2=[O:21])[C:9]([F:22])=[CH:8][C:7]=1[C:26]#[N:27])([CH3:3])[CH3:2]
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Reactant: N#C[Cu]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(C#N)cc2F)c(=O)n1C
Temperature: 195 °C
Reaction time: 0.75 h

Procedure:
A mixture of 50.0 g of 2-chloro-5-[3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoic acid isopropyl ester and 25.4 g of copper(I) cyanide in 225 ml of dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is heated for 2.5 hours at 195° C. under nitrogen. The mixture is then cooled to room temperature and 2 l of ethyl acetate are added. The mixture is then poured onto 1.31 of water and 300 ml of 32% hydrochloric acid, and the whole is stirred for 45 minutes at room temperature until two distinct layers have formed. The organic phase is removed, washed twice with 200 ml of water each time and dried over anhydrous sodium sulfate. Concentration by evaporation of the organic solution yields crystalline 2-cyano-5-[3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoic acid isopropyl ester, m.p. 188°-200° C.
Reaction SMILES: [C:1]1([N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:36][CH:35]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:27]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:43]5[CH:44]=[CH:45][C:40]([C:37]6[CH:38]=[CH:39][CH:34]=[CH:35][CH:36]=6)=[CH:41][CH:42]=5)[N:21]=4)=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Nc1nccc(-c2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)cc2)n1
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(Nc3nccc(-c4ccc(-c5ccc(N(c6ccccc6)c6ccccc6)cc5)cc4)n3)cc2)cc1
Yield: 91.9 %

Procedure:
4-(4′-Diphenylaminobiphenyl-4-yl)pyrimidine-2-amine (100 mg, 0.24 mmol), 4-bromobiphenyl (61.5 mg, 0.264 mmol), dichlorobis(triphenylphosphine)palladium(II) (17 mg, 0.024 mmol), Xantphos (14 mg, 0.024 mmol) and sodium t-butoxide (35 mg, 0.36 mmol) were added in toluene (3 mL), refluxed under nitrogen atmosphere for 14 hours. This solution was cooled, and the precipitated solid was filtered and washed with cold toluene and water to obtain the title compound (125 mg).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[I-].[Na+].Cl[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].CC1C=C(OC)C=CC=1>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[O:7]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)CCl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: COc1cccc(C)c1
Product: CCOC(=O)COc1ccccc1
Reaction time: 1.25 h

Procedure:
The three-necked 500 mL flask was filled with phenol (1.89 g, 20 millimoles, Aldrich, 99+%), sodium hydroxide (1.76 g, 50% w/w solution in water, 22 millimoles, Aldrich), sodium iodide (0.18 g, 1 millimole, Aldrich, 98%), and water (196.78 g) and immersed in the water bath kept at 60° C. The excess molar concentration of sodium hydroxide was 0.10. The mixture was stirred mechanically at 600 rpm. Next, the organic phase consisting of ethyl chloroacetate (9.84 g, 80 millimoles, Aldrich, 99%), Aliquat 336 (0.834 g, 2 millimoles, and 3-methylanisole (GC standard, 0.490 g, 4 millimoles, Aldrich, 99%) was introduced into the flask. The organic phase: aqueous phase weight ratio was 1:18. The stirring was continued at 60° C. for several hours. The aliquots were taken every 60-90 minutes and briefly centrifuged. The organic phase was injected into the GC instrument. The yield of ethyl phnoxyacetate after 390 minutes retention time was 18%.
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])[C:6]([C:17]([F:20])([F:19])[F:18])=[CH:5]1)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[H][H]>C(OCC)C>[F:20][C:17]([F:18])([F:19])[C:6]1[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[CH:8][NH:4][CH:5]=1
Reactant: [H][H]
Reactant: CC(=O)n1cc(-c2cccc(Cl)c2Cl)c(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: FC(F)(F)c1c[nH]cc1-c1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
29.0 g of N-acetyl-4-(2,3-dichlorophenyl)-3-trifluoromethylpyrrole are dissolved in 500 ml of diethyl ether. This solution is subsequently cooled to 0° C., and to it are added portionwise 13.7 g of lithium aluminium hydride. The mixture is afterwards stirred for 1 hour, and there are then added dropwise at 5° C. 55 ml of 4% sodium hydroxide solution, in the course of which elementary hydrogen is given off, and the mixture is subsequently stirred for a further hour at room temperature. The mixture is then filtered; the filtrate is dried over magnesium sulfate, again filtered, and concentrated by evaporation. The resulting oil is distilled at 150°/8×10-5 mbar. By covering it with hexane, there is obtained from the distillate 3-trifluoromethyl-4-(2,3-dichlorophenyl)pyrrole in the form of colourless crystals, m.p. 63°-65° C.
Reaction SMILES: N([O-])=O.[Na+].[F:5][CH:6]([F:20])[O:7][C:8]1[C:9]([F:19])=[C:10]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[C:11]([NH-])=[O:12].[OH2:21]>S(=O)(=O)(O)O>[F:5][CH:6]([F:20])[O:7][C:8]1[C:9]([F:19])=[C:10]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[C:11]([OH:21])=[O:12]
Reactant: O
Reactant: [NH-]C(=O)c1cc(F)c(F)c(OC(F)F)c1F
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1cc(F)c(F)c(OC(F)F)c1F
Temperature: 25 °C

Procedure:
30 ml of an aqueous solution containing 6.60 g (0.096 moles) of sodium nitrite were slowly added dropwise, whilst stirring and ice-cooling, to a suspension of 15.53 g (0.064 moles) of 3-difluoromethoxy-2,4,5-trifluorobenzoyl amide [(XXVI), X=X'F, R16 --NH2 ] [prepared as described in step (b) above] in 20 ml of concentrated aqueous sulfuric acid, and the mixture was heated under reflux for 30 minutes. At the end of this time, it was cooled to room temperature, and then 50 ml of water were added it. The reaction mixture was then extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure, to give 15.59 g of 3-difluoromethoxy-2,4,5-trifluorobenzoic acid as a colorless powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:24](Br)[CH2:25][OH:26]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:24][CH2:25][OH:26])[CH2:11][CH2:12]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCN1CCN(c2ccccn2)CC1

Procedure:
To a mixture of 1-(2-pyridyl)piperazine (5 g), potassium carbonate powder (9 g) and N,N-dimethylformamide (30 ml) was added dropwise ethylene bromohydrin (5.74 g) under stirring. The mixture was stirred at room temperature for 6 hours, diluted with water (100 ml) and extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel chromatography [eluent: dichloromethane-methanol (95:5)] to give 4-(2-pyridyl)-1-piperazineethanol as crystals, m.p. 82.5°-84° C. Yield 4.68 g (73.7%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][O:6][C:5](=[O:7])[C:4]1[CH:3]=[C:2]([I:1])[C:10]([O:11][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)=[C:9]([I:12])[CH:8]=1
Reactant: BrCc1cccc(Br)c1
Reactant: O=C(O)c1cc(I)c(O)c(I)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(OCc1cccc(Br)c1)c1cc(I)c(OCc2cccc(Br)c2)c(I)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.8 %

Procedure:
A suspension of 3,5-diiodo-4-hydroxybenzoic acid (0.39 g, 1.0 mmol), 3-bromobenzyl bromide (0.62 g, 2.5 mmol), and cesium carbonate (0.98 g, 3.0 mmol) in 10 mL DMF was stirred for 15 hours at room temperature. The mixture was then poured into 1 M HCl (100 mL) and a white precipitate formed. The precipitate was isolated by filtration and was recrystallized from hot isopropanol/chloroform, yielding the title compound as bright white crystals (610 mg, 84%). 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 2H), 7.88 (d, J=7.6 Hz, 1H), 7.62 (d, J=8 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.47-7.34 (m, 3H), 7.26-7.21 (m, 2H), 5.44 (s, 2H), 5.15 (s, 2H). TLC (9:1 Hex:EtOAc), Rf 0.49.
Reaction SMILES: CCCP(=O)=O.[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[NH:17][C:18]1[N:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][N:19]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:39]2[CH2:40][CH2:41][N:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=3)[CH2:37][CH2:38]2)=[O:14])=[CH:10][C:9]=1[NH:17][C:18]1[N:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][N:19]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2cccnc2)n1
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N2CCN(c3ccccn3)CC2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution containing ˜50% of propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μL, ˜1 mmol) is added within 20 minutes to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (214.4 mg, 0.7 mmol), 1-(2-pyridyl)piperazine (Aldrich, Buchs, Switzerland; 114.3 mg, 0.7 mmol) and triethylamine (776 μL, 5.6 mmol) in 2 mL N,N-dimethylformamide. After stirring for 24 hours at room temperature, the mixture is treated with a half-saturated aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The solvent is evaporated off under reduced pressure and the residue dried in vacuo. The crude product is purified by column chromatography on silica gel, eluent 5-10% methanol in dichloromethane, to give the title compound as a solid. 1H-NMR (400 MHz, DMSO-d6, δ): 2.31 (s, 3H); 3.35-3.74 (m, 8H); 6.65 (ddd, 1H); 6.79 (d, 1H); 7.13 (dd, 1H); 7.32 (d, 1H); 7.44 (d, 1H); 7.49-7.56 (m, 2H); 7.69 (m, 1H); 8.11 (m, 1H); 8.40 (m, 1H); 8.52 (d, 1H); 8.66 (dd, 1H); 9.06 (s, 1H); 9.24 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.C(C1C=CC(S([N:20]=[N+:21]=[N-])(=O)=O)=CC=1)(O)=O.[N:23]([CH:26]1[CH:29]([CH2:30][C:31](=[O:43])[CH2:32][C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[NH:28][C:27]1=[O:44])=[N+:24]=[N-:25]>C(#N)C.C(OC(=O)C)C>[N:23]([CH:26]1[CH:29]([CH2:30][C:31](=[O:43])[C:32]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])=[N+:20]=[N-:21])[NH:28][C:27]1=[O:44])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: [N-]=[N+]=NC1C(=O)NC1CC(=O)CC(=O)OCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC1C(=O)NC1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
Triethylamine (15 mmol) is added to an ice-cold stirring suspension of p-carboxybenzene sulfonylazide (5 mmol) and 3-azido-4-(3-benzyloxycarbonyl-2-oxopropyl)-azetidin-2-one (5 mmol) in anhydrous acetonitrile (30 ml). The resulting mixture is stirred at room temperature for 90 mins, then diluted with ethylacetate and filtered. The filtrate is washed with water, 0.5 N sodium hydroxide, water, and brine, dried over magnesium sulfate, filtered, and evaporated under vacuum to give 3-azido-4-(3-benzyloxycarbonyl-3-diazo-2-oxopropyl)-azetidin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[N:15]=[CH:14][C:13]([CH3:19])=[C:12](Cl)[C:11]=3[CH:10]=[CH:9]2)=[CH:5][CH:4]=1.[CH3:23][NH:24][C:25]1[N:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=2)[N:26]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C(Cl)Cl.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[N:15]=[CH:14][C:13]([CH3:19])=[C:12]([C:30]4[CH:31]=[C:32]5[C:27](=[CH:28][CH:29]=4)[N:26]=[C:25]([NH:24][CH3:23])[N:34]=[CH:33]5)[C:11]=3[CH:10]=[CH:9]2)=[CH:5][CH:4]=1
Reactant: CNc1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Reactant: COc1ccc(Cn2ccc3c(Cl)c(C)cnc3c2=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CNc1ncc2cc(-c3c(C)cnc4c(=O)n(Cc5ccc(OC)cc5)ccc34)ccc2n1
Temperature: 145 °C
Yield: 90.3 %

Procedure:
A mixture of 7-(4-methoxybenzyl)-4-chloro-3-methyl-1,7-naphthyridin-8(7H)-one (0.750 g, 2.38 mmol), N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (0.815 g, 2.86 mmol), dichlorobis(triphenyl-phosphine)palladium (ii) (0.0836 g, 0.119 mmol) and sodium carbonate (0.758 g, 7.15 mmol) was placed in a clear microwave vial along with 10 ml of a combination of 7:3:2 DME:H2O:EtOH. The vial was capped and heated in a Personal Chemistry SmithSynthesizer to 145° C. for 10 minutes. The reaction was diluted with DCM:MeOH (2:1) and the insoluble were filtered off The filtrate was loaded directly on silica gel and purified by column chromatography on silica gel using a gradient of 0 to 10% MeOH in DCM to give 7-(4-methoxybenzyl)-3-methyl-4-(2-(methylamino)quinazolin-6-yl)-1,7-naphthyridin-8(7H)-one (0.940 g, 90.2% yield) as a yellow solid. MS(M+H)− 438.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@@H:8]1[CH2:19][OH:20])([CH3:4])[CH3:3].[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C.O>C(OCC)(=O)C>[CH3:4][C:2]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[C@@H:8]1[CH2:19][O:20][S:24]([CH3:23])(=[O:26])=[O:25])([CH3:1])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,1-dimethylethyl (2R,3S)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-(hydroxymethyl)-1-pyrrolidinecarboxylate (Registry No. 156129-73-6, 4.0 g) in ethyl acetate (100 mL), methanesulfonyl chloride (1.12 mL) and triethylamine (2.19 mL) was added at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes. The reaction mixture was added by water and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated, obtained the title compound (4.87 g) having the following physical properties.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][S:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:7]=1)[CH3:2].C(N(CC)CC)C.[Cl:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:42](=[O:43])[C:41]3[CH:45]=[CH:46][C:38]([Cl:37])=[CH:39][CH:40]=3)=[CH:17][C:16]=2[CH2:22][S:23][CH2:24][C:25]([F:26])([F:27])[F:28])[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CSCC(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CSCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To {3-[4-amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.200 g, 0.47 mmol) and triethylamine (0.08 mL, 0.56 mmol) in CH2Cl2 was added 4-chlorobenzoyl chloride (0.07 mL, 0.56 mmol), and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated and used directly in the hydrolysis step.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][CH:20]([OH:32])[CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:12]=1>C(Cl)Cl>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][C:20](=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:12]=1
Reactant: OC(CCCCOC1CCCCO1)CCCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(CCCCOC1CCCCO1)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.62 ml (22.73 mmol) of dimethylsulfoxide in 60 ml dry methylene chloride is cooled to -78° and 1.44 ml (16.53 mmol) oxalyl chloride is added dropwise. The mixture is stirred for 0.5 h at -78° and a solution of 1.0 g (3.31 mmol) of 1-(3-pyridyl)-4-hydroxy-8-(2-tetrahydropyranyloxy)-octane [=5-hydroxy-8-(3-pyridyl)-1-(2-tetrahydropyranyloxy)-octane, see example 37] in 15 ml dry methylene chloride is added and the mixture is stirred for 10 min at -78°. The mixture is warmed to -60° and maintained for 15 min at that temperature. The reaction is quenched by the addition of 6.9 ml triethylamine. The cold bath is removed and the mixture allowed to warm to room temperature. The reaction mixture is extracted with 150 ml methylene chloride and washed with saturated sodium bicarbonate solution. The organic phase is dried, filtered, concentrated and chromatographed using 3:2 ethyl acetate/hexane to yield 1-(3-pyridyl)-4-oxo-8-(2-tetrahydropyranyloxy)-octane; NMR (CDCl3): delta 2.6 (t,2H), 2.4 (t,4H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[NH:15]1[CH2:18][CH:17]([CH2:19][OH:20])[CH2:16]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:15]3[CH2:18][CH:17]([CH2:19][OH:20])[CH2:16]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: OCC1CNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: OCC1CN(c2ccc3nnc(C(F)(F)F)n3n2)C1
Yield: 30.2 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (4.44 g, 20.0 mmol), azetidin-3-ylmethanol (2.25 g, 22.0 mmol) and DIPEA (5.21 mL, 30.0 mmol) in DMF (40 mL) was heated at 70° C. for 1 hour. The solution was evaporated and partitioned between water and 2M aqueous K2CO3. The organic phase was washed with water and brine and dried over MgSO4. The crude product was purified by MPLC silica chromatography, eluting with 5% MeOH in DCM. Pure fractions were evaporated to dryness and triturated with ether, giving [1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]azetidin-3-yl]methanol (1.65 g, 30%) as a cream crystalline solid.
Reaction SMILES: [C:1]1(=[O:13])[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1.[CH3:14][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>C1(C)C=CC=CC=1>[OH:13][C:1]1([CH3:14])[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1
Reactant: O=C1CCn2c1cc1ccccc12
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(O)CCn2c1cc1ccccc12
Reaction time: 0.08 h

Procedure:
To 2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (613 mg, 3.58 mmol) suspended in toluene (12 mL), at 0° C. there was added methyl magnesium bromide 1.5M in toluene/THF (75:25) (3.0 mL, 4.5 mmol). The mixture was stirred at 0° for 5 minutes, then at room temperature for 20 minutes. After quenching with saturated aqueous NH4Cl solution, the mixture was partitioned between H2O and EtOAc. The crude product obtained from the organic fraction was chromatographed on a column of silica gel eluting with a 1:2 mixture of EtOAc and hexane to afford the title product as a yellow oil.