Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13](O)=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C@H:64]1[C@@H:67]([CH2:68][N:69]2[C:73]([CH3:74])=[N:72][N:71]=[N:70]2)[NH:66][C:65]1=[O:75]>C(Cl)Cl.CN(C=O)C>[C:25]([O:24][C:22]([NH:21][C:18]1[S:19][CH:20]=[C:16](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:29])/[C:13]([NH:63][C@@H:64]2[C:65](=[O:75])[NH:66][C@@H:67]2[CH2:68][N:69]2[C:73]([CH3:74])=[N:72][N:71]=[N:70]2)=[O:14])[N:17]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Reactant: Cc1nnnn1C[C@H]1NC(=O)[C@H]1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nnnn1C[C@H]1NC(=O)[C@H]1NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
Prepared in an analogous manner to example 4, step 3 using (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (130 mg, 0.302 mmol), DIPEA (158 μL, 0.906 mmol) and HATU (115 mg, 0.302 mmol) in DCM:DMF (2:1, 3.0 mL) at 0° C. followed by a solution of (3S,4R)-3-amino-4-((5-methyl-1H-tetrazol-1-yl)methyl)azetidin-2-one (55 mg, 0.30 mmol) in DCM:DMF (2:1, 3.0 mL). After stirring at rt for 1 h it was concentrated in vacuo, dissolved in EtOAc, washed with water then brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (Acetone-DCM), affording the title compound (133 mg, 74%) as a solid. LCMS: Rt=0.92 min, m/z=594.2 (M+1) Method 2m_acidic.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[C:8]3[C:13]4[CH:14]=[CH:15][C:16]([O:18]C)=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.C(S)(S)C.[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>ClCCl.O>[F:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)[C:8]3[C:13]4[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1
Reactant: COc1ccc2c3c(sc2c1)Nc1cc(F)ccc1N=C3N1CCN(C)CC1
Agent: CC(S)S
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CN1CCN(C2=Nc3ccc(F)cc3Nc3sc4cc(O)ccc4c32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
8-Fluoro-3-methoxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine (500 mg) was dissolved in dichloromethane (15 ml) and ethanedithiol (2.10 ml) and aluminium chloride (2.51 g) were added. The mixture was stirred at room temperature for 2 hours. Water (50 ml) was added to the reaction mixture and 10% aqueous sodium hydroxide solution was added until it assumed alkaline. The mixture was extracted with chloroform, washed with water, washed with saturated aqeuous sodium chloride solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated by silica gel column chromatography (chloroform:methanol=5:1) and recrystallized from ethyl acetate to give 8-fluoro-3-hydroxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine (251 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[C:12]2[OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)CC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:20]([O-:22])=[O:21])=[C:12]2[OH:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccnc2ccc(OCc3ccccc3)cc12
Reactant: O=[N+]([O-])O
Solvent: CCC(=O)O
Product: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1O
Temperature: 110 °C

Procedure:
A mixture of 6-benzyloxyquinolin-4-ol (65.7 g) and propionic acid (660 mL) was heated at 110° C. with vigorous stirring. Nitric acid (19.2 mL of 16 M) was slowly added over a period of 30 minutes while maintaining the reaction temperature below 120° C. After the addition, the reaction was allowed to cool to ambient temperature. The resulting solid was isolated by filtration, washed sequentially with propionic acid, isopropanol, and diethyl ether. The material was dried in a vacuum dessicator for 2 days to provide 46.0 g of 6-benzyloxy-3-nitroquinolin-4-ol as a tan powder.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([C:17]4[C:18]([NH:23][C:24]5[C:25]([CH3:43])=[CH:26][CH:27]=[C:28]6[C:33]=5[N:32]=[CH:31][N:30]=[C:29]6[NH:34][C:35]5[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=5)=[N:19][CH:20]=[CH:21][CH:22]=4)=[C:11]3[CH:10]=[N:9]2)=CC=1>C(O)(C(F)(F)F)=O>[NH:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([C:17]3[C:18]([NH:23][C:24]4[C:25]([CH3:43])=[CH:26][CH:27]=[C:28]5[C:33]=4[N:32]=[CH:31][N:30]=[C:29]5[NH:34][C:35]4[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=4)=[N:19][CH:20]=[CH:21][CH:22]=3)=[C:11]2[CH:10]=[N:9]1
Reactant: COc1ccc(Cn2ncc3c(-c4cccnc4Nc4c(C)ccc5c(Nc6ccc(C#N)cc6)ncnc45)ncnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(Nc3ccc(C#N)cc3)ncnc2c1Nc1ncccc1-c1ncnc2[nH]ncc12
Temperature: 65 °C

Procedure:
A mixture of 4-(8-(3-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-ylamino)-7-methylquinazolin-4-ylamino)benzonitrile (120 mg, 203 μmol) in TFA (3 ml) was heated at 65° C. for 3 hr. TFA was removed under vacuum. MeOH (2N, NH3) (20 ml) was added and then solvent was removed under vacuum. The product was purified by flash chromatography eluting with MeOH/DCM (1-5%) to give 4-(8-(3-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-ylamino)-7-methylquinazolin-4-ylamino)benzonitrile. MS (ESI pos. ion) m/z 471 (M+H+).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:39][C:40]1[S:44][N:43]=[C:42]([CH3:45])[CH:41]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(OCC)(=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:32])[NH:39][C:40]5[S:44][N:43]=[C:42]([CH3:45])[CH:41]=5)=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Reactant: Cc1cc(N)sn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)c2ccc(Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)c([N+](=O)[O-])c2)sn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.8 %

Procedure:
A solution of the product of Example 19C (290 mg, 0.546 mmol) in anhydrous tetrahydrofuran (5 mL) was treated with 5-amino-3-methylisothiazole hydrochloride (90.5 mg, 0.6008 mmol) and diisopropylethylamine (0.238 mL, 1.365 mmol), and stirred at room temperature under a nitrogen atmosphere for 18 hours. The reaction was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (25 mL), water (2×25 mL), and brine (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide the title compound (202 mg, 61%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].[Cl:14][C:15]1[CH:22]=[C:21](I)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:14][C:15]1[CH:22]=[C:21]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: N#Cc1ccc(I)cc1Cl
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc(C#N)c(Cl)c2)C1=O
Yield: 32.1 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465 mmol) was reacted with 2-chloro-4-iodo-benzonitrile (245.3 mg. 0.9311 mmol), 1,4-dioxane (20 mL), copper iodide (16.1 mg, 0.08465 mmol), trans-1,2-diamino cyclohexane (12.6 mg, 0.1100 mmol) and potassium phosphate (30.6 mL, 0.254 mmol) to afford the crude product which was purified by column chromatography on silica gel (2% MeOH in CHCl3). The residue was washed with hexane and dried to afford 85 mg of the product (32% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[CH:14][C:6]1[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[O:9][C:5]=1[CH:4]=2.[Br:19]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[C:3]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[CH:14][C:6]1[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[O:9][C:5]=1[CH:4]=2
Reactant: Cc1cccc2cc3c(cc12)oc1ccccc13
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2cc3c(cc12)oc1ccccc13
Yield: 101 %

Procedure:
To a RB flask was added 7-methyl-benzo[b]naphtho-[2,3-d]furan (Cambridge Chemicals, Inc., 16.0 g, 0.07 mol), N-bromosuccinimide (Aldrich 12.8 g, 0.072 mol, recrystallized from H2O and dried under high vacuum overnight), a catalytic amount of benzoyl peroxide (0.01 g) and CCl4 (1 L). The mixture was refluxed for 2.5 h, cooled and filtered to remove the succinimide formed in the reaction. The solvent was then removed from the reaction mixture by rotary evaporation. The crude product was purified by flush chromatography on SiO2 using PhCH3 as the eluting solvent. The appropriate fractions were combined and the solvent once again removed by rotary evaporation to give 22.0 g of product. The material (which was one spot by TLC and pure by NMR) was used without further purification.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[N:13]O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO.[Ni](Cl)Cl>[C:1]1([CH:7]2[CH2:8][CH2:9][CH:10]([NH2:13])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ON=C1CCC(c2ccccc2)CC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC1CCC(c2ccccc2)CC1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a stirred solution of Intermediate 13 (5.1 g) and nickel chloride (12.8 g) in methanol (40 ml) at −30° C., was added sodium borohydride (10.2 g). The reaction was stirred at −30° C. for 30 min, before being stirred at room temperature for 16 h. The solvent was removed in vacuo, and the black slurry was dissolved in aqueous hydrochloric acid (2M, 300 ml), and washed with ethyl acetate (3×200 ml). The aqueous layer was then basified to pH 10 using solid sodium hydroxide, and EDTA added until the solution stayed blue. The aqueous was then extracted with ethyl acetate (3×200 ml), the combined organic extracts dried over magnesium sulphate (4 g), and the solvent removed in vacuo to yield the title compound as a white oily solid (3.2 g).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.Cl[Si:17]([CH3:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[CH3:18][Si:17]([CH3:20])([CH3:19])[N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8]
Reactant: O=C1CCCCCN1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)N1CCCCCC1=O

Procedure:
Caprolactam, which is commercially available, (10.0 g, 88.0 mmol), Et3N (14.8 mL, 106 mmol) and chlorotrimethylsilane (13.5 mL, 106 mmol) were dissolved in toluene (60 mL) and refluxed under Ar for 3 h. The reaction was filtered and concentrated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18](O)[N:17]3[N:21]=[CH:22][CH:23]=[C:16]3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:35]>>[C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([Cl:35])[N:17]3[N:21]=[CH:22][CH:23]=[C:16]3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)C1CCC(c2cc(O)n3nccc3n2)CC1
Solvent: CN(C)c1ccccc1
Product: CC(C)(C)OC(=O)C1CCC(c2cc(Cl)n3nccc3n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
4-(7-Hydroxy-pyrazolo[1,5-a]pyrimidin-5-yl)-cyclohexanecarboxylic acid t-butyl ester (Int-7b, 10.6 g), N,N-dimethylaniline (15.0 ml) and POCl3 (120 mL) were mixed and stirred at room temperature for 18 hours. The solution was reduced in vacuo and cooled to 0° C. in ice bath. The reaction was then quenched with sat. NaHCO3(aq) and extracted with DCM (100 mL×3). The combined organics were dried with Na2SO4 and the solvent was removed in vacuo. The resulting oil was purified via silica gel column on 20% to 100% ethyl acetate in hexanes gradient to yield the title compound (2.5 g, 32% over three steps). LC-MS: 336 [M+H].
Reaction SMILES: O.NN.[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=1>C(O)C.[Pd]>[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[O:12][C:13]1[N:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=1
Reactant: Cc1cccc(C)c1Oc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc(C)c1Oc1ccc(N)cn1
Temperature: 90 °C
Reaction time: 3 h
Yield: 190.7 %

Procedure:
In a 50 mL round-bottomed flask 2-[(2,6-dimethylphenyl)oxy]-5-nitropyridine (Intermediate 41, 555.9 mg) was dissolved in ethanol (10 mL) to give a pale orange solution. Palladium on carbon (230 mg, 0.216 mmol) and hydrazine hydrate (0.416 mL, 4.32 mmol) were added. The reaction mixture was stirred at 90° C. After 3 hours the reaction was completed. The reaction mixture was filtered and the organic phase was evaporated under vacuum to afford 929.9 mg of a dark orange solid that was charged on a 10 g SCX cartridge. It was then flushed with 200 mL of ethanol followed by 50 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated under vacuum to afford the title compound as dark orange solid (447.6 mg).
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.[Cl:23][C:24]1[CH:29]=[C:28](Cl)[N:27]=[C:26]([S:31][CH3:32])[N:25]=1.[F:33][C:34]1[CH:35]=[CH:36][C:37]([S:43][CH3:44])=[C:38](B(O)O)[CH:39]=1>>[Cl:23][C:24]1[CH:29]=[C:28]([C:36]2[CH:35]=[C:34]([F:33])[CH:39]=[CH:38][C:37]=2[S:43][CH3:44])[N:27]=[C:26]([S:31][CH3:32])[N:25]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: CSc1ccc(F)cc1B(O)O
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: CSc1nc(Cl)cc(-c2cc(F)ccc2SC)n1

Procedure:
Method as described for intermediate 5 using 4,6-dichloro-2-(methylthio)pyrimidine and 5-fluoro-2-(methylthio)phenylboronic acid. The residue was purified further by flash chromatography (0-10% EtOAc in petroleum ether (40:60) to afford 4-chloro-6-(5-fluoro-2-(methylthio)phenyl)-2-(methylthio)pyrimidine as a white solid, (500 mg, 42%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[CH:28]=[CH:27][C:26]=1B(O)O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([C:26]3[CH:27]=[CH:28][C:29]([C:31]([O:33][CH3:34])=[O:32])=[CH:30][C:25]=3[F:24])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(B(O)O)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(Cl)ncc2Cl)CC1
Product: COC(=O)c1ccc(-c2cc(C#CC3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)cn2)c(F)c1

Procedure:
The title compound is prepared from 4-(2,5-dichloro-pyridin-4-ylethynyl)-piperidine-1-carboxylic acid tert-butyl ester and 2-fluoro-4-methoxycarbonyl-phenylboronic acid following a procedure analogous to that described for Intermediate 14. LC (method 7): tR=1.76 min; Mass spectrum (ESI+): m/z=473 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([Cl:25])[C:5]([C:6]([C:8]2[C:16]3[C:11](=[C:12]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[N:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[O:7])=[C:4]([Cl:26])[CH:3]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:25][C:23]1[CH:24]=[C:2]([C:31]2[CH:32]=[N:27][CH:28]=[N:29][CH:30]=2)[CH:3]=[C:4]([Cl:26])[C:5]=1[C:6]([C:8]1[C:16]2[C:11](=[C:12]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:7]
Reactant: OB(O)c1cncnc1
Reactant: O=C(c1c(Cl)cc(Br)cc1Cl)c1c[nH]c2c(NC(=O)C3CC3)nccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1c(Cl)cc(-c2cncnc2)cc1Cl)c1c[nH]c2c(NC(=O)C3CC3)nccc12
Temperature: 100 °C
Yield: 14.4 %

Procedure:
A mixture of N-[3-(4-bromo-2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropanecarboxamide (108 mg, 0.23 mmol), pyrimidin-5-yl-boronic acid (42 mg, 0.34 mmol), potassium carbonate (95.22 mg, 0.69 mmol), water (0.5 mL) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (34.8 mg, 0.047 mmol) in 1,4 dioxane (3 mL) was heated overnight at 100° C. in a sealed vial. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The resulting crude mass was purified by preparative thin layer chloromatography using 10% methanol in dichloromethane to afford N-{3-[2,6-dichloro-4-(pyrimidin-5-yl)benzoyl]-1H-pyrrolo[2,3-c]pyridin-7yl}cyclopropane carboxamide (15 mg, 14.01%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=2[O:19][CH3:20])=[CH:4][CH:3]=1>C1COCC1.[Ni]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=2[O:19][CH3:20])=[CH:6][CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])cc1C(=O)Nc1ccc(Br)cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1ccc(N)cc1C(=O)Nc1ccc(Br)cc1
Reaction time: 20 h

Procedure:
A mixture of N-(4-bromophenyl)-2-methoxy-5-nitro-benzoic acid amide (930 mg, 2.6 mmol) and 140 mg Ra-Ni in 40 mL THF was stirred for 20 h under an atmosphere of hydrogen (3 bar). After filtration and concentration i. vac. the subtitle compound was obtained. Yield: 890 mg (quantitative). MS [M+H]+=321 (Br-isotope pattern); TLC: Rf=0.60 (silica gel, DCM:EtOH 9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([O:23][CH2:24][C:25]#[N:26])[C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:6]([F:8])[CH:7]=1.S(C)C.CO>C1COCC1>[NH2:26][CH2:25][CH2:24][O:23][C@@H:9]([C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC#N)c2cc(F)cc(Cl)c2)C1
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cc(F)cc(Cl)c2)C1
Temperature: 0 °C
Yield: 27.9 %

Procedure:
(R)-tert-Butyl 3-((R)-(3-chloro-5-fluorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylate (4.4 g, 10.2 mmol, crude) was dissolved in anhydrous THF (60 mL), and the solution was heated to reflux under nitrogen. A solution of 10 M of BH3.Me2S (3 mL, 30.6 mmol) in THF was added dropwise and stirring was continued under reflux overnight. The resulting solution was cooled to 0° C., CH3OH was added dropwise to quench the reaction. Evaporation of the solvent to give the crude product, which was purified by silica column to give (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chloro-5-fluorophenyl)methyl)piperidine-1-carboxylate (1.1 g, yield 28%), which was used in the next step without further purification.
Reaction SMILES: S(Cl)(Cl)=O.C(OCCC(O)=O)C.C(OCCC(Cl)=O)C.[CH2:21]([O:23][CH2:24][CH2:25][C:26]([N:28]=[C:29]=[S:30])=[O:27])[CH3:22].[Cl:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][C:38]=1[O:39][C:40]1[C:49]2[C:44](=[CH:45][C:46]([O:52][CH3:53])=[C:47]([O:50][CH3:51])[CH:48]=2)[N:43]=[CH:42][CH:41]=1)[NH2:35]>C(O)C.C1(C)C=CC=CC=1>[Cl:31][C:32]1[CH:33]=[C:34]([NH:35][C:29]([NH:28][C:26](=[O:27])[CH2:25][CH2:24][O:23][CH2:21][CH3:22])=[S:30])[CH:36]=[CH:37][C:38]=1[O:39][C:40]1[C:49]2[C:44](=[CH:45][C:46]([O:52][CH3:53])=[C:47]([O:50][CH3:51])[CH:48]=2)[N:43]=[CH:42][CH:41]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: CCOCCC(=O)N=C=S
Agent: CCOCCC(=O)Cl
Agent: CCOCCC(=O)O
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOCCC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(Cl)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3-ethoxypropanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3-ethoxypropanoyl isothiocyanate was prepared using the resultant 3-ethoxypropanoyl chloride as a starting compound according to the description of the literature. 3-Ethoxypropanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (46 mg, yield 62%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5=[N:34][N:35]=[C:36]([CH3:37])[N:23]5[CH:22]=[CH:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.[ClH:39].CCOC(C)=O>CO.C(Cl)Cl>[ClH:39].[CH3:37][C:36]1[N:23]2[C:24]([C:25]3[CH:26]=[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:18]([C:15]4[CH:14]=[CH:13][C:12]([C:8]5([NH2:7])[CH2:9][CH2:10][CH2:11]5)=[CH:17][CH:16]=4)=[N:19][C:20]=3[CH:21]=[CH:22]2)=[N:34][N:35]=1
Reactant: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)nc3ccn12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5(N)CCC5)cc4)nc3ccn12
Temperature: 25 °C

Procedure:
To a solution of tert-butyl{1-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (1-6f) (9.23 g, 18.26 mmol) in MeOH (20 mL) and DCM (100 mL) was added a 4N solution of HCl in EtOAc (91 mL, 365 mmol). The sealed reaction mixture was permitted to stir at room temperature. After 18 hours the reaction mixture was filtered to give 1-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutanamine hydrochloride (1-17) as an off-white solid. HRMS (M+H)+: observed=406.2047, calculated=406.2026.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([OH:14])=O.S(Cl)(Cl)=O.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:14]
Reactant: Cc1c(C(=O)O)sc2nc[nH]c(=O)c12
Reactant: C1CCNC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N2CCCC2)sc2nc[nH]c(=O)c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
To a cooled (0° C.) solution of pure 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid, (0.1 g, 0.47 mmol) in DMF (5 mL) was added dropwise thionyl chloride (0.034 mL, 0.47 mmol). The reaction mixture was stirred at 0° C. for 15 min. Pyrrolidine (0.12 mL, 1.4 mmol) was then added and the reaction was allowed to warm to RT over 1 h. The reaction mixture was quenched with saturated NaHCO3 (25 mL) and extracted with EtOAc (25 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated to give 0.080 g of pure 5-methyl-6-(pyrrolidine-1-carbonyl)thieno[2,3-d]pyrimidin-4(3H)-one, (yield: 65%).