Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[OH:13][C:14]1[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH3:24])/[CH:20]=[CH:21]/[CH2:22][OH:23])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:24])[CH:20]=[CH:21][CH2:22][OH:23])=[CH:25][CH:26]=1)[CH:11]=[N:10]2
Reactant: Clc1ccc2nc(Cl)cnc2c1
Reactant: CC(/C=C/CO)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C=CCO)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 1.99 g (10 mmol) of 2,6-dichloroquinoxaline, 2.13 g (11 mmol) of (E)-4-(4-hydroxyphenoxy)-2-penten-1-ol, 1.73 g (12.5 mmol) of powdered, anhydrous potassium carbonate and 50 ml of dry acetonitrile was warmed at reflux under nitrogen for a period of 3 hours. The mixture was cooled to room temperature, and the solid filtered off and washed well with ether. The filtrates were combined and evaporated to dryness, and the residue partitioned between ether and 2 percent aqueous sodium hydroxide. The aqueous layer was separated and extracted again with ether. The combined organic layers were washed with water, dried over MgSO4 and evaporated to dryness. The residual solid was purified by preparative scale HPLC, eluting with 7:3 hexane:ethyl acetate, to give a solid which was recrystallized from toluene. This gave 2.60 g (73%) of the desired pentenol as pale yellow crystals, having a melting point (m.p.) of 124°-126° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:35]([CH2:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)[CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([NH:42]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:43][CH:44]=1)[CH3:36])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(Cc1ccccc1)Cc1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)Cc2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-benzyl-N-methyl-aminomethyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) C32H29N3O3
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>O1CCCC1.CO>[CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=3[C:13]=2[CH3:14])[OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2cccc(F)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(O)C2CCCCC2)oc2cccc(F)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclohexyl(4-fluoro-3-methyl-1-benzofuran-2-yl)methanone (2.6 g) synthesized in the above-mentioned (1) was dissolved to in tetrahydrofuran (40 mL) and methanol (4 mL), and sodium borohydride (90%, 0.83 g) was added to the solution under ice-cooling. The ice bath was removed, the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (5 mL) and 1N hydrochloric acid (10 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (2.5 g, quantitative) as a pale-yellow oil.
Reaction SMILES: C[CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/C)C)C)[CH3:3].CC([CH2:25][CH2:26][CH2:27][C@H:28]([C@@H:30]1[C@:48]2(C)[C@H:33]([C@H:34]3[C@H:45]([CH2:46][CH2:47]2)[C@]2(C)[C:37]([CH2:38][C@H:39](CC2)[OH:40])=[CH:36][CH2:35]3)[CH2:32][CH2:31]1)C)C>O>[C:39]([O:21][CH2:20][CH2:19][CH2:17][CH2:16][CH2:15][CH2:14][CH2:12][CH2:11][CH2:10][CH2:9][CH2:7][CH2:6][CH2:5][CH2:4][CH2:2][CH3:3])(=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:45][CH2:46][CH2:47][CH2:48][CH2:33][CH2:32][CH2:31][CH2:30][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC

Procedure:
The encapsulant is soluble in the polymerizer, and solid at room temperature. Examples of encapsulants are polymers and waxes. Waxes include waxy polymers. Waxes are water insoluble, organic materials that are solid or semi-solid at room temperature and usually of lower density than water, and typically can be melted above room temperature to form a liquid. Preferred waxes include any naturally occurring and synthetic waxes, wax esters, and greases that generally have a melting temperature of 30° C. or more with a melting range of less than 10° C. and are usually non-reactive with the reagents or solvents to which they are exposed. Examples of waxes are esters of various long-chain (fatty) alcohols and long-chain acids, preferably where at least one member of the ester has 10 or more carbon atoms, including various unsaturated and branched chain types and also those esters of glycerols and sterols. Also, certain free alcohols or acids have wax-like properties of melting temperature and inertness. Examples of saturated fatty acids that can be used are capric, lauric, myristic, palmitic, margaric, stearic, arachidic, behenic, tetracosanic, lignoceric, cerotic, and melissic. Some examples of unsaturated fatty acids that can be used are tiglic, hypogaeic, gaidic, physetoleic, elaidic, oleic, isooleic, erudic, brassidic, and isoerudic. Some examples of fatty alcohols that can be used are octadecyl, carnaubyl, ceryl, melissyl, and phytol. Also included are various esters of these and other fatty acids with any suitable fatty alcohols, or sterols such as cholesterol, or glycerols. Other examples are natural or suitably modified or derivatized waxes such as various plant derived waxes, greases and oils including carnauba wax, cranberry wax, ouricuri wax, candelilla wax, raphia wax, apple, cotton and cactus waxes; waxes (including greases) produced by bacteria (e.g. cetyl stearate); fungi, protozoa and algae; various invertebrate waxes and greases including insect waxes such as beeswaxes (e.g. triacontyl palmitate, palmatyl palmitate), and Coccus sp. derived waxes (e.g. lac, cochineal and Chinese insect); other animal fats (e.g. triglycerides) and waxes including spermaceti (e.g. cetyl palmitate), lanolin and wool grease.
Reaction SMILES: [N:1]1([CH:6]2[CH:10]([OH:11])[CH2:9][NH:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[N:17][CH:18]=1.C(N(C(C)C)CC)(C)C>C(#N)C.C(=O)(O)[O-].[Na+]>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([N:8]2[CH2:9][C@@H:10]([OH:11])[C@H:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:7]2)=[N:17][CH:18]=1
Reactant: Fc1ccc(Br)cn1
Reactant: OC1CNCC1N1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O[C@@H]1CN(c2ccc(Br)cn2)C[C@H]1N1CCCC1
Yield: 67.6 %

Procedure:
Dissolve [1,3′]bipyrrolidinyl-4′-ol (452 mg, 2.89 mmol) in acetonitrile (10 mL) and add 5-bromo-2-fluoro-pyridine (764 mg, 4.34 mmol) and diisopropylethylamine (1.26 mL, 7.23 mmol). Reflux the mixture for 3 days. Dilute the mixture with saturated sodium bicarbonate and extract with dichloromethane (3×). Combine the organic fractions, dry over sodium sulfate, filter, and evaporate. Purify by silica gel chromatography, eluting with 0-7.5% methanol (2N NH3)/CH2Cl2 to give 610 mg (67%) of the title compound as a yellow foam. MS/ES m/z (79Br) 312.0 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@@H:10]([OH:31])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:39]([Si:43]([CH3:46])([CH3:45])Cl)([CH3:42])([CH3:41])[CH3:40].N1C=CN=C1>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C@@H:10]([O:31][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:46])[CH3:45])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:22]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)O[Si](C)(C)C(C)(C)C

Procedure:
1.4 g (2.69 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-benzyloxyphenyl)methyl]-hexanoic acid in 2.9 ml of DMF are stirred, at RT for 18 h, together with 1.87 g (12.4 mmol) of tert-butyldimethylchlorosilane and 1.5 g (22 mmol) of imidazole. The reaction mixture is then poured onto ice water, and this mixture is extracted with 3 portions of ethyl acetate; the combined organic phases are washed with 10% citric acid solution, water and saline, dried with sodium sulfate and evaporated. An oil is obtained. This is followed by hydrolysis of the silyl ester function of the oil, at RT, using 2.2 g of potassium carbonate in 63 ml of methanol/water/THF,3:1:1, and partial evaporation at RT. The aqueous residue is poured onto 10% citric acid solution and ice, and this mixture is extracted 3 times with ethyl acetate; the organic phases are washed twice with water and saline, dried with sodium sulfate and evaporated. Column chromatography (SiO2, D) of the crude product yields the title compound: TLC Rf (D)=0.17; tRet (I)=33.7 min; FAB-NS (M+H)+ =634.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]([CH3:46])([CH3:45])[O:38]C3CCCCO3)=[CH:29][CH:28]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C>S(=O)(=O)(O)O.C1COCC1.O>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]([CH3:46])([OH:38])[CH3:45])=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][OH:17]
Reactant: CC(C)(CCCCc1ccc(C=Cc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)cc1)OC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)CCCCc1ccc(C=Cc2ccc(CO)c(CO)c2)cc1

Procedure:
In a manner similar to Example 25(d), by reacting 10 drops of concentrated sulphuric acid with 265 mg (0.4 mmol) of 2-[5-(4-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl]vinyl}phenyl)-1,1-dimethylpentyloxy]tetrahydropyran in 5 ml of THF and 5 ml of water, white crystals (m=73 mg; Y=51%) are obtained. m.p.=102-4° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(CC)C(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16]
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)O)sc1Cl
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 500 mL round-bottomed flask was added 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (6 g, 21.65 mmol), 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (7.25 g, 21.65 mmol) [prepared according to the procedure of Preparation 6], N,N-diisopropyl ethylamine (5.67 ml, 32.5 mmol) and Pybrop (15.08 g, 32.5 mmol) in Dichloromethane (DCM) (150 ml). After stirring at RT for 12 h, the reaction solution was washed with H2O (2×100 mL) and the organic layer was dried Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with [EtOAc/hexanes, 1:1] to give the product [9.0 g, 74%] as a white solid: LCMS (ES) m/z 558 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([OH:16])[CH2:12][N:13]([CH3:15])[CH3:14])=[CH:2]1.[C:17]1(C)[CH:22]=CC(S(O)(=O)=O)=C[CH:18]=1>CC(C)=O>[CH3:14][N:13]([CH2:12][CH:11]1[O:16][C:17]([CH3:22])([CH3:18])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10]1)=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH3:15]
Reactant: CN(C)CC(O)Cc1c[nH]c2ccccc12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CN(C)CC1Cc2c([nH]c3ccccc23)C(C)(C)O1

Procedure:
A mixtue of 1-(indol-3-yl)-3-(dimethylamino)propan-2-ol [9.5 g, 0.00435 mole, described by Z. G. Starostina et al., Khim.-Farm. Zh., 6, 14(1972) (Chem. Abstr., 78, 58185 r)] and p-toluenesulfonic acid (10 g, 0.0525 mole) in dry acetone (100 ml), is refluxed for 24 hours. The reaction mixture is evaporated and the residue is dissolved in water. The aqueous acidic solution is extracted with diethyl ether and the aqueous phase is basified with a saturated solution of sodium carbonate. The alkaline aqueous phase is extracted with diethyl ether and the organic extract is dried over magnesium sulfate, treated with charcoal and evaporated to give a residue of 3-[(dimethylamino)methyl]-1,3,4,9-tetrahydro-1,1-dimethylpyrano-[3,4-b]indole, a compound of formula II. The hydrochloride salt of the latter compound is crystallized from acetonitrite, mp 213°-215° C.
Reaction SMILES: [C:1](O)(C(F)(F)F)=[O:2].[CH2:8]([N:10]([CH2:36][CH3:37])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:27]3[CH2:33][CH:32]4[N:34](C)[CH:29]([CH2:30][CH2:31]4)[CH2:28]3)[C:18]3[C:23]([O:24][C:25]=2[CH:26]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:12])[CH3:9].ClC(OC(Cl)C)=O>C(Cl)Cl>[CH2:8]([N:10]([CH2:36][CH3:37])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:27]3[CH2:33][CH:32]4[NH:34][CH:29]([CH2:30][CH2:31]4)[CH2:28]3)[C:18]3[C:23]([O:24][C:25]=2[CH:26]=1)=[C:22]([O:2][CH3:1])[CH:21]=[CH:20][CH:19]=3)=[O:12])[CH3:9]
Reactant: O=C(O)C(F)(F)F
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1N2C1CC2CCC(C1)N2C
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(OC)cccc1N2C1CC2CCC(C1)N2
Yield: 44.8 %

Procedure:
To a solution of the TFA salt of 10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid diethylamide, 4e (110 mg, 0.25 mmol) in methylene chloride (10 mL) was added 1-chloroethyl chloroformate (0.58 mL, 0.75 mmol). The mixture was heated to reflux for 2 h. The mixture was evaporated, dissolved in methanol (5 mL), and heated for 2 h at reflux. Water was added, and the solution was extracted with methylene chloride. The organic phase was separated, evaporated, and purified via reverse phase HPLC to yield 69 mg (44.8%) of title compound 10-(8-aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-10H-phenoxazine-3-carboxylic acid diethylamide, 5e, as a TFA salt. MS m/z=422 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[C:25]3[C:20](=[C:21]([CH2:26][S:27][CH3:28])[CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH3:9])=[C:4]([F:29])[CH:3]=1.ClC1C=CC(C(C2C=CC(Cl)=CC=2)C2C3C(=C(CS(C)=[O:49])C=CC=3)NC=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[C:25]3[C:20](=[C:21]([CH2:26][S:27]([CH3:28])=[O:49])[CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH3:9])=[C:4]([F:29])[CH:3]=1
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Reactant: CSCc1cccc2c(C(C)(c3ccc(F)cc3)c3ccc(Cl)cc3F)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(C)(c3ccc(F)cc3)c3ccc(Cl)cc3F)c[nH]c12

Procedure:
The title compound was prepared starting from 300 mg (0.70 mmol) of the compound from Example 290 in analogy to the synthesis of the compound from Example 296. 258 mg (83% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[NH:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.Cl[C:14]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:18]([CH3:27])[N:17]=[N:16][C:15]=1[CH3:28]>C(OCC)(=O)C>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]2[C:14]([C:12]3[CH:11]=[CH:10][NH:9][N:8]=3)=[C:15]([CH3:28])[N:16]=[N:17][C:18]=2[CH3:27])=[CH:25][CH:24]=1
Reactant: c1cn[nH]c1
Reactant: Cc1nnc(C)c(-c2ccc(Cl)cc2)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nnc(C)c(-c2cc[nH]n2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
87 mg of sodium hydride (55% oil dispersion) was added to 5 ml of DMF. To this was added 0.14 g of pyrazole, and the mixture was stirred for 0.5 hours at room temperature. To the resultant mixture was added 0.25 g of 4-chloro-5-(4-chlorophenyl)-3,6-dimethylpyridazine, and the mixture was stirred for 3 hours on an oil bath of 80° C. To the reaction mixture was added ethyl acetate, and the mixture was washed with brine four times. The organic layer was dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.38 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.19 g of 5-(4-chloro-phenyl)-3,6-dimethyl-4-pyrazolylpyridazine (hereinafter, described as compound (6) of the present invention.).
Reaction SMILES: [C:1]([N:3]=[CH:4]OCC)#[N:2].[C:8]([C:10]1[CH:23]=[CH:22][C:13]2[O:14][C:15]([CH3:21])([CH3:20])[C@@H:16]([OH:19])[C@H:17]([NH2:18])[C:12]=2[CH:11]=1)#[N:9]>C(OCC)(=O)C>[C:8]([C:10]1[CH:23]=[CH:22][C:13]2[O:14][C:15]([CH3:21])([CH3:20])[C@@H:16]([OH:19])[C@H:17]([NH:18][CH:4]=[N:3][C:1]#[N:2])[C:12]=2[CH:11]=1)#[N:9]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: CCOC=NC#N
Solvent: CCOC(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC=NC#N)[C@@H]1O
Reaction time: 2 h

Procedure:
To 1.18 g of ethyl N-cyanoformimidate, 2.29 g of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-amino-2H-benzo[b]pyran-3-ol was added, and the mixture was reacted under stirring at a temperature of from 100° to 120° C. for 2 hours. The reaction mixture was cooled, then dissolved in 100 ml of ethyl acetate, washed twice with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The residual solid was recrystallized from methylene chloride/isopropanol/petroleum ether to obtain 1.75 g of the above identified compound in the form of crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:10]=[C:9]([C:11]([OH:13])=O)[S:8][C:6]=2[N:7]=1.C(Cl)(=O)C(Cl)=O.CCN(CC)CC.[NH:33]1[CH2:36][CH:35]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH2:34]1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:10]=[C:9]([C:11]([N:33]3[CH2:36][CH:35]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[CH2:34]3)=[O:13])[S:8][C:6]=2[N:7]=1
Reactant: C1CN(C2CNC2)CCO1
Reactant: O=C(O)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1nc2c(N3CCOCC3)nc(Cl)nc2s1)N1CC(N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a suspension of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carboxylic acid (301 mg, 1.0 mmol) in DCM (6 mL) was added oxalyl chloride (847 μL, 10.00 mmol) and the resulting mixture allowed to stir at r.t. for 1 h then concentrated in vacuo and azeotroped with toluene. The resulting yellow solid was suspended in a mixture of DCM (6 mL) and NEt3 (418 μL, 3.00 mmol) at 0° C. before the addition of 4-azetidin-3-ylmorpholine (142 mg, 1.00 mmol). The resulting mixture was warmed to r.t. after 1 h then stirred for a further 30 min. The reaction mixture was partitioned between DCM and H2O, the organic phase dried (Na2SO4) and concentrated in vacuo. The resulting residue was triturated with EtOAc and dried in vacuo affording the title compound as an off-white solid (269 mg, 63%). LCMS (method H): RT 2.19 min [M+H]+ 425.3
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[N:12]1([C:18]2[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]3[NH:26][N:27]=[CH:28][C:19]=23)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:29]([O:33][C:34]([N:36]([CH:49]([CH3:51])[CH3:50])[CH2:37][C@H:38]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[C:39](O)=[O:40])=[O:35])([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:48][C:45]1[CH:46]=[CH:47][C:42]([C@H:38]([C:39]([N:15]2[CH2:16][CH2:17][N:12]([C:18]3[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]4[NH:26][N:27]=[CH:28][C:19]=34)[CH2:13][CH2:14]2)=[O:40])[CH2:37][N:36]([CH:49]([CH3:50])[CH3:51])[C:34](=[O:35])[O:33][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:43][CH:44]=1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: N#Cc1cnc2[nH]ncc2c1N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(C#N)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
DIEA (d 0.742; 0.102 mL, 0.585 mmol) was added to a solution of 4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile dihydrochloride (0.0661 g, 0.219 mmol), (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.050 g, 0.146 mmol, see Example B) and TBTU (0.0564 g, 0.176 mmol) in DCM (1 mL) and stirred at room temperature for 18 hours. The mixture was directly loaded onto a silica column and purified by chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-cyano-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.2 mL) was added. The mixture was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-4-(4-(2-(4-chlorophenyl)-3-(isopropylamino)propanoyl)piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile dihydrochloride (0.043 g, 56%). MS APCI (+) m/z 452.1 detected.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[OH:52][CH:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.CCN(C(C)C)C(C)C>C1COCC1>[OH:52][CH:53]1[CH2:58][CH2:57][N:56]([C:16]([C:14]2[S:15][C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])=[CH:12][CH:13]=2)=[O:18])[CH2:55][CH2:54]1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(C(=O)O)s2)s1
Reactant: OC1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccc(C(=O)N3CCC(O)CC3)s2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
5-[2-(Acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-carboxylic acid, Compound (4) (50 mg; 0.18 mmol; 1 eq.), is dissolved in THF (8 ml). PyBOP (138.2 mg; 0.27 mmol; 1.50 eq.), 4-hydroxypiperidine (53.7 mg; 0.53 mmol; 3 eq.) and DIEA (0.06 ml; 0.35 mmol; 2 eq.) are added successively. The reaction mixture is stirred at room temperature for 2 hours. The solvents are evaporated and the crude product is suspended in MeCN, filtered and washed several times with MeCN, affording Compound (7) as brown solid (15.2 mg; 23%). 1H NMR (DMSO-d6) δ 1.30-1.45 (m, 2H), 1.72-1.85 (m, 2H), 2.14 (s, 3H), 2.42 (s, 3H), 3.25-3.38 (m, 2H), 3.75 (m, 1H), 3.85-4.02 (m, 2H), 4.80 (d, J=6 Hz, 1H), 7.13 (d, J=6 Hz, 1H), 7.36 (d, J=6 Hz, 1H), 12.18 (br s, 1H). M−(ESI): 364.12; M+(ESI): 366.10. HPLC, Rt: 2.35 min (purity: 97.9%).