Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([F:8])[CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.[OH-].[Na+]>CO>[CH2:19]([NH:1][CH2:2][C@@H:3]1[C@H:7]([F:8])[CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(OCc1ccccc1)N1C[C@H](CNCc2ccccc2)[C@H](F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3S,4S)-3-Aminomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine (1.10 g) was dissolved in methanol (13 mL). To this solution, molecular sieves 4A (440 mg) and benzaldehyde (0.44 mL) were sequentially added and the mixture was stirred at room temperature for 1 hour. Subsequently, a borane-pyridine complex (0.44 mL) was added and the mixture was further stirred at room temperature for 3.5 hours. This was followed by addition of 6 mol/L hydrochloric acid (7.3 mL) and stirring at room temperature for 1 hour. Subsequently, a 30% aqueous solution of sodium hydroxide was added to make the mixture basic and the mixture was extracted with diethyl ether (2×100 mL). The diethyl ether extracts were combined and the combined diethyl ether layer was dried over anhydrous sodium sulfate and was then concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=hexane:ethyl acetate=4:1 shifted to 1:1) to give 1.18 g of (3S,4S)-3-benzylaminomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine as a colorless tar-like product.
Reaction SMILES: CCCCCC[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13]S([O-])(=O)=O.[Na+].[CH:19]([Cl:22])([Cl:21])[Cl:20].C(O)CC(C)C>C(O)C(N)(CO)CO.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>[C:12]1([OH:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1.[C:12]1([OH:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1.[CH:19]([Cl:22])([Cl:21])[Cl:20]
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: NC(CO)(CO)CO
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)CCO
Product: Oc1ccccc1

Procedure:
catarrhalis cell pellet was resuspended in 20 mL Tris-EDTA (TE) buffer, pH 7.5. Pronase (final concentration 500 μg/mL) and SDS (final concentration 1%) were added and the suspension was incubated in a 37° C. water bath for 2 hours. DNA was isolated by sequential extractions with phenol (1 time), phenol-chloroform (1:1, 2 times), and chloroform-isoamyl alcohol (24:1, 1 time). Extracted DNA was dialyzed against 1M NaCl at 4° C. for 4 hours. This was followed by dialysis against TE buffer, pH 7.5, at 4° C. for 48 hours (3 buffer changes). DNA was ethanol precipitated from the dialysate. Large size DNA was collected by spooling on a glass rod. Air dried DNA was dissolved in 3 mL water. Small scale Sau3A (New England BioLabs) restriction digests of chromosomal DNA (final volume 10 μl) were done to establish conditions required to obtain maximal amounts of chromosomal DNA with a size range of 15-23 kb. Large scale digests were prepared once the optimal digestion conditions were defined. The large scale digests consisted of 50 μl chromosomal DNA (290 μg/mL), 33 μL water, 10 μL Sau3A buffer (New England BioLabs), 1 μL BSA (10 mg/ml, New England BioLabs) and 6.3 μL Sau3A (0.04 U/μL), and were incubated at 37° C. for 15 minutes. Reactions were stopped with the addition of 10 μL 10X loading buffer (100 mM Tris-HCl pH 8, 10 mM EDTA, 0.1% bromophenol blue, 50% glycerol). Digested DNA was applied to 0.5% agarose gels (prepared in Tris-acetate-EDTA (TAE)) and separated according to size at 50 V for 6 hours. The region of the gel encompassing DNA of size 15-23 kb was cut from the gel and placed in dialysis tubing (BRL) with 3 mL TAE. DNA was electroeluted from the gel slice overnight at a field strength of 1 V/cm. Electroeluted DNA in TAE was extracted once with phenol, once with phenol-chloroform (1:1), and finally precipitated with ethanol. The dried DNA pellet was dissolved in 5 μL water. Size-fractionated chromosomal DNA was ligated with BamHI cut EMBL3 arms (Promega) using T4 DNA ligase in a final volume of 9 μL. The entire ligation reaction was packaged into phage λ using a commercially purchased packaging kit following the manufacturer's (Amersham) protocol.
Reaction SMILES: CS([O-])(=O)=O.[O:6]([CH:13]1[CH2:16][NH:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].[CH3:19][N:20]=[C:21]=[O:22]>C1C=CC=CC=1>[CH3:19][NH:20][C:21]([N:15]1[CH2:16][CH:13]([O:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14]1)=[O:22]
Reactant: CN=C=O
Reactant: c1ccc(OC2CNC2)cc1
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CNC(=O)N1CC(Oc2ccccc2)C1

Procedure:
The methanesulfonate of 3-phenoxyazetidine (10.5 g., 0.043 mole) was partitioned between 50 ml of benzene and 25 ml. of dilute sodium hydroxide. The benzene layer was dried over calcium sulfate and filtered. The filtrate was treated with 2.6 g. (0.043 mole) of methylisocyanate and the solution was stirred at room temperature for 18 hours. The resulting mixture was concentrated at reduced pressure and the residue was crystallized from a mixture of ethyl acetate-isopropyl ether to give 1.2 g. (14%) of product (m.p. 139°-141° C.).
Reaction SMILES: S(=O)(=O)(O)O.Br[C:7]12[CH2:14][CH2:13][C:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([CH2:11][CH2:12]1)[CH2:9][CH2:8]2.[CH:20]([OH:22])=[O:21]>S([O-])([O-])(=O)=O.[Ag+2]>[CH2:15]([C:10]12[CH2:13][CH2:14][C:7]([C:20]([OH:22])=[O:21])([CH2:12][CH2:11]1)[CH2:8][CH2:9]2)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCC12CCC(Br)(CC1)CC2
Reactant: O=CO
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: CCCCCC12CCC(C(=O)O)(CC1)CC2
Temperature: 5 °C

Procedure:
In another flask, 150 ml of concentrated sulfuric acid and 1.3 g of silver sulfate (Ag2SO4) were mixed and cooled to 5° C., and 5 ml of a solutoin of 3 g of the aforesaid 1-bromo-4-pentylbicyclo(2,2,2)octane in n--C6H14 was added. Subsequently, 1 ml of 98% HCOOH was gradually added thereto. After the evolution of gas ceased, the reaction solution was added to 600 ml of ice water to deposit crystals. The crystals were collected by filtration to obtain 4-pentylbicyclo[2,2,2]octanecarboxylic acid.
Reaction SMILES: [CH3:1][SiH:2]([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].[CH2:9]([NH2:12])[CH:10]=[CH2:11]>[Rh]>[NH2:12][CH2:9][CH2:10][CH2:11][Si:2]([CH3:1])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5]
Reactant: C=CCN
Reactant: CCO[SiH](C)OCC
Agent: [Rh]
Product: CCO[Si](C)(CCCN)OCC
Yield: 78 %

Procedure:
There is considerable prior art relating to the synthesis of poly(aminoalkylmethylsiloxanes). Generally, poly(aminoalkylmethylsiloxanes) have been produced by first preparing aminoalkylmethyldialkoxysilanes, followed by hydrolysis with or without an endblocking agent, such as a trimethylsilyl derivative, to form cyclic and linear poly(3-aminoalkylmethylsiloxanes). The isomeric purity of the poly(aminoalkylmethylsiloxane) fluids, prepared in the manner of the prior art, is dependent upon the isomeric purity of the aminoalkylmethyldialkoxysilane prepared in the first step of the synthesis. German Patent No. 2408480 describes the reaction of a silazane derivative from allylamine and an organohydrochlorosilane, in the presence of a proton acceptor to form an intermediate silazane which then undergoes a hydrosilylation reaction catalyzed by a platinum catalyst. Upon alcoholysis, the intermediate hydrosilylation product forms 3-aminopropylmethyldiethoxysilane in 70% overall yield. A molar excess of at least 50% of allylamine is used in this process. Identification of the beta-isomer in the product was not made. Japanese Patent No. 10017578 describes another method of synthesis by hydrosilylation of N,N-bis(trimethylsilyl)allylamine by methyldimethoxysilane. The product of that reaction is then heated with methanol to form 3-aminopropylmethyldimethoxysilane in at least 85% overall yield. The presence of the beta-isomer in the product was not made. Japanese Patent No. 11209384 describes the use of a rhodium:cyclooctadiene complex as a hydrosilylation catalyst for the addition of methyldiethoxysilane to allylamine to form 3-aminopropylmethyldiethoxysilane in 78% yield. 2-Aminopropylmethyldiethoxysilane is formed at very low levels in this process not exceeding 0.5%. U.S. Pat. No. 5,391,675 describes the formation of an aminopropylmethylsiloxy-containing polydimethylsiloxane by barium or strontium hydroxide catalyzed condensation of a silanol terminated polydimethylsiloxane with a 3-aminopropylalkoxysilane with elimination of an alcohol.
Reaction SMILES: [NH2:1][C:2]1[C:10](Br)=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([NH:31][C:32]([C:34]2[CH:38]=[CH:37][S:36][CH:35]=2)=[O:33])[CH:25]=[CH:24]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[NH2:6])=[CH:7][C:8]([CH3:12])=[CH:9][C:10]=1[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([NH:31][C:32]([C:34]1[CH:38]=[CH:37][S:36][CH:35]=1)=[O:33])[CH:25]=[CH:24]2
Reactant: Cc1cc(Br)c(N)c(C(N)=O)c1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(N)=O)c(N)c(-c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)c1
Temperature: 25 °C
Yield: 10 %

Procedure:
2-amino-3-bromo-5-methylbenzamide (31.8 mg, 0.139 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (122 mg, 0.370 mmol), Fibercat palladium catalyst (Johnson-Matthey, 68.2 mg), and K2CO3 (2 M in water, 0.51 ml, 1.0 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.5 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C for 20 minutes. The reaction was then cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (4×10 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified via silica gel (Biotage instrument, 13%->50%->100% EtOAc/hexanes) to afford title compound (5.6 mg, 10%). MS (ESI pos. ion) m/z: 402 (M+H). Calc'd Exact Mass for C23H19N3O2S: 401.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:8]([C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH2:18][C:19]2=[O:22])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].[CH2:23]=O>C(O)C.Cl>[C:8]([C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([CH2:23][N:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)[C:19]2=[O:22])=[CH:14][CH:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)CCC2
Reactant: C1CCNCC1
Reactant: C=O
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1ccc2c(c1)C(=O)C(CN1CCCCC1)CC2
Yield: 42.9 %

Procedure:
Piperidine hydrochloride (8.9 g, 0.073 mol), 7-tert-butyl-1,2,3,4-tetrahydronaphthalene-1-one (7.0 g, 0.035 mol) and paraformaldehyde (2.2 g, 0.073 mol) were refluxed together in ethanol (150 ml) along with concentrated hydrochloric acid (1 ml) as a catalyst for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in water then extracted with diethyl ether. The resulting aqueous solution was neutralized with sodium bicarbonate and extracted with diethyl ether (2×200 ml), dried over magnesium sulphate and concentrated under reduced pressure to give 7-tert-butyl-2-piperidinomethyl-1,2,3,4-tetrahydronaphthalen-1-one (4.5 g, 43% yield) as a buff coloured solid melting at 62°-3°. Compound number 4 in Table I.
Reaction SMILES: [C:1]([NH:6][CH:7](Cl)[C:8]([O:10]C)=[O:9])([O:3][CH2:4][CH3:5])=[O:2].[CH3:13][Si:14]([C:17]#[C:18][Si](C)(C)C)([CH3:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl>[CH3:1][C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13].[C:1]([NH:6][CH2:7][C:8]([O-:10])=[O:9])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Reactant: CCOC(=O)NC(Cl)C(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC#C[Si](C)(C)C
Product: CCOC(=O)NCC(=O)[O-]
Temperature: 25 °C

Procedure:
To 19.5 g (0.1 M) of methyl N-carbethoxy-2-chloroglycinate and 17.0 g (0.1 M) of bis-trimethylsilyl acetylene in 200 ml of methylene chloride at 0° C is added 13.5 g (0.1 M) of aluminum chloride and the reaction mixture is allowed to warm to 25° C. After 24 hours at 25° C water is carefully added to the mixture which is then extracted with methylene chloride. The combined organic solutions are dried over magnesium sulfate, concentrated and distilled with the b.p. 100°/0.15 mm fraction collected to give methyl 2-trimethylsilylacetylene-2-carbethoxyaminoacetate.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][C:10]([OH:12])=O)=[O:6])[CH3:3].[F:23][C:24]([F:35])([F:34])[C:25]1[N:29]2[CH2:30][CH2:31][NH:32][CH2:33][C:28]2=[N:27][N:26]=1>>[CH3:22][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][C:10]([N:32]1[CH2:31][CH2:30][N:29]2[C:25]([C:24]([F:35])([F:23])[F:34])=[N:26][N:27]=[C:28]2[CH2:33]1)=[O:12])=[O:6])[CH3:3]
Reactant: FC(F)(F)c1nnc2n1CCNC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)ccc1F
Yield: 48.7 %

Procedure:
The title compound was prepared from (3R)-3-[(1,1-dimethylethoxycarbonyl)-amino]-4-(2,5-difluorophenyl)butanoic acid (Intermediate 1, 50 mg, 0.16 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine (30 mg, 0.16 mmol) using a procedure analogous to that described for Example 1, Step C. The crude product was purified by preparative TLC (silica gel, 100% ethyl acetate, then 10% methanol/dichloromethane (2×)) to afford the title compound (38.1 mg) as a solid. 1H NMR (500 MHz, CDCl3) δ 1.38 (s, 9H), 2.57˜3.05 (m, 4H), 3.85˜4.30 (m, 5H), 4.90 (s, 1H), 4.95˜5.15 (m, 1H), 5.22˜5.40 (br, 1H), 6.86˜7.24 (m, 3H). LC/MS (M+1-t-Boc) 390.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([C:15]([CH2:26][CH3:27])([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=3)[CH2:16][CH3:17])=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].Br[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:20]([CH3:25])[CH:19]=3)([CH2:26][CH3:27])[CH2:16][CH3:17])=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(O)c(C)c3)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)ccc2s1
Yield: 94.7 %

Procedure:
5-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-benzo[b]thiophene-2-carboxylic acid ethyl ester (5.97 g, 15.6 mmol), 1-bromopinacolone (4.20 g, 23.4 mmol), and K2CO3 (6.46 g, 46.8 mmol) in acetone (100 mL) are reacted analogous to Example 1D to provide the title compound (7.10 g, 95%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH2:30][OH:31])[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[CH:30]=[O:31])[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1C=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(hydroxymethyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (510 mg, 1.017 mmol) in CH2Cl2 (20 mL) at 0° C. under N2, was added Dess-Martin periodinane (647 mg, 1.526 mmol) portionwise. The reaction was stirred at 0° C. for 1 h. The reaction was carefully quenched with saturated NaHCO3 and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give 2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)benzaldehyde as a white solid. LCMS calc.=500.1; found=500.0 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 10.29 (s, 1H); 8.04 (d, J=7.8 Hz, 1H); 7.93 (s, 1H); 7.85 (d, J=8.0 Hz, 1H); 7.83 (s, 1H); 7.82 (s, 2H); 5.77 (d, J=7.9 Hz, 1H); 5.11 (d, J=16.5 Hz, 1H); 4.94 (d, J=16.5 Hz, 1H); 4.23-4.18 (m, 1H); 0.84 (d, J=6.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N+:11]([O-])=O)=[CH:4][N:3]=1.[CH3:14][CH:15]1[CH2:19][CH2:18][CH:17]([CH3:20])[NH:16]1.[H][H].C1CCCCC=1>C(O)C.[Pd]>[ClH:1].[ClH:1].[NH2:8][C:7]1[C:2]([N:16]2[CH:17]([CH3:20])[CH2:18][CH2:19][CH:15]2[CH3:14])=[N:3][CH:4]=[C:5]([NH2:11])[CH:6]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CC1CCC(C)N1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CC1CCC(C)N1c1ncc(N)cc1N
Product: Cl

Procedure:
1.5 g (5.63 mmol) of (2,5-dimethylpyrrolidin-1-yl)-3,5-dinitropyridine, obtained according to Protocol A from 2-chloro-3,5-dinitropyridine and 2,5-dimethylpyrrolidine, were reduced by hydrogen transfer in 50 ml of ethanol in the presence of palladium-on-charcoal and 5 ml of cyclohexene. 900 mg of N-(3,5-diaminopyrid-2-yl)-2,5-dimethylpyrrolidine dihydrochloride were obtained.
Reaction SMILES: [P:1]([Br:4])(Br)[Br:2].[N:5]1([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1>N1C=CC=CC=1>[Br:2][P:1]([Br:4])[C:15]1[CH:14]=[N:13][CH:12]=[CH:11][C:10]=1[N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: BrP(Br)Br
Reactant: c1cc(N2CCCC2)ccn1
Solvent: c1ccncc1
Product: BrP(Br)c1cnccc1N1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of PBr3 (8.8 g, 32.5 mm) in 100 mL of pyridine was treated with 4-pyrrolidinopyridine (5.0 g, 33.7 mm) over a period of 5 min. The resulting mixture was then stirred at room temperature for 3 days to give the crude 3-dibromophosphino-4-pyrrolidinopyridine (31P NMR: δ152.2 ppm). This compound was used directly for the next step without further purification. Next, polymer-supported secondary amines from Example 1 (9.0 g, 1.1 mmol/g, 9.9 mmol) was slowly added into the mixture above while stirring at room temperature for a period of 10 min. The resulting suspension was refluxed overnight before the solution was filtered off. The resin was washed with THF (2×50 mL), hexane (3×50 mL), CH2Cl2 (4×50 mL), and hexane (2×50 mL). The resulting resin was dried in vacuum overnight to yield the polymer-supported 3-P(Br)-4-(NC4H8)C5H3N. 31P NMR (202 MHz, CDCl3): δ168.4 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][Cl:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:28][CH2:27][CH2:26][CH2:25][CH2:24][O:19][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([NH:6][C:5]3[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][C:4]=3[F:22])=[N:8][CH:9]=[N:10]2)=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: ClCCCCBr
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCCCl
Temperature: 40 °C
Yield: 78.5 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (3.6 g, 11.3 mmol), (prepared as described for the starting material in Example 4), 1 bromo-4-chlorobutane (1.95 ml, 16.9 mmol) and potassium carbonate (4.66 g, 33.8 mmol) in DMF (75 ml) was heated at 40° C. for 4 hours. The mixture was allowed to cool and was partitioned between methylene chloride and water. The aqueous layer was adjusted to pH7 with 2M hydrochloric acid. The organic layer was separated, washed with brine, dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/ethyl acetate (1/1). The purified solid product was triturated with pentane, collected by filtration and dried under vacuum to give 7-(4-chlorobutoxy)-4(4chloro-2-fluoroanilino)-6-methoxyquinazoline (3.64 g, 79%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:17])[C:9](=[O:16])[N:10]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:23][CH:22]=[CH:21][N:20]=1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:11][N:10]1[C:5]2[C:6](=[N:7][C:2]([C:24]3[C:19]([F:18])=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:3][CH:4]=2)[N:8]([CH3:17])[C:9]1=[O:16]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1F
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(Cl)nc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccnc3F)nc21
Temperature: 90 °C

Procedure:
To a microwave vial was added 5-chloro-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (14-1) (25 mg, 0.1 mmol), 2-fluoro-3-(tributylstannanyl)pyridine (55 mg, 0.15 mmol), and bis(tri-t-butylphosphine)palladium(0) (10 mg, 0.02 mmol). The reagents were purged with nitrogen, dissolved in DMF (0.5 ml), and heated at 90° C. overnight. The reaction was cooled to room temperature, diluted with methanol, and passed through a syringe filter. The solution was purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile) and the desired fractions were collected and concentrated to produce 1-(2,2-dimethylpropyl)-5-(2-fluoropyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (22-1). HRMS (M+H)+: observed=315.1618, calculated=315.1616.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([C:26]1[N:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[NH2:25]>CCCCCCC.C(O)C.CC(O)C>[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([NH:25][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:26]1[N:27]=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC(C)CC(N)c1cccnn1
Solvent: CC(C)O
Solvent: CCO
Solvent: CCCCCCC
Product: CC(C)CC(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1cccnn1

Procedure:
The title compound was synthesized in analogy to Example 47 b), using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) and 3-methyl-1-(pyridazin-3-yl)butan-1-amine as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using a mixture of heptane, ethanol and 2-propanol as eluent. The (+)-enantiomer was isolated. MS (EI): m/e=432.5 [MH+].