Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([C:41]2([NH2:44])[CH2:43][CH2:42]2)[N:35]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:40][C:38]1[CH:39]=[C:34]([CH3:33])[N:35]=[C:36]([C:41]2([NH:44][C:26]([C:25]3[C:24]([O:30][CH3:31])=[CH:23][C:22]([CH3:32])=[C:21]([C:18]4[CH:19]=[CH:20][C:10]5[O:9][C:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)=[C:12]([C:13]([NH:14][CH3:15])=[O:16])[C:11]=5[CH:17]=4)[CH:29]=3)=[O:27])[CH2:42][CH2:43]2)[N:37]=1
Reactant: Cc1cc(C)nc(C2(N)CC2)n1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nc(C)cc(C)n5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.15 g, 0.34 mmol, 1 eq), 1-(4,6-dimethylpyrimidin-2-yl)cyclopropanamine (0.17 g, 0.1 mmol, 3 eq) (60% purity), HOBT (0.046 g, 0.34 mmol, 1.0 eq), EDC.HCl (0.072 g, 0.37 mmol, 1.1 g) in DCM at ambient temperature under a nitrogen atmosphere was added diisopropylethylamine (0.132 g, 1.0 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and finally purified by preparative HPLC. Yield: 0.15 g (14%). 1H NMR (400 MHz, DMSO-d6): δ 1.43-1.44 (d, J=3.36 Hz, 2H), 1.51-1.54 (d, J=3.48 Hz, 2H), 2.32-2.34 (d, J=5.8 Hz, 9H), 2.81-2.82 (d, J=4.6 Hz, 3H), 4.0 (s, 3H) 7.0 (s, 1H), 7.15 (s, 1H), 7.34-7.42 (m, 3H), 7.52 (s, 1H), 7.72-7.74 (d, J=8.8 Hz, 2H), 7.97-8.02 (m, 2H), 8.46-8.48 (d, J=4.56 Hz, 1H), 8.91 (s, 1H). LCMS: (ES+) m/z=579.2 (M+H)+
Reaction SMILES: [Li+].[F:2][C:3]1[C:11]([O:12][C:13]2[C:14]3[CH:21]=[C:20]([C:22]4[CH:30]=[CH:29][C:25]([C:26]([O-:28])=O)=[CH:24][CH:23]=4)[NH:19][C:15]=3[N:16]=[CH:17][N:18]=2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:31])[NH:7]2.[CH2:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH3:33].C(OP(C#N)(=O)OCC)C>CN(C=O)C.CCOC(C)=O>[CH2:32]([N:34]1[CH2:39][CH2:38][N:37]([C:26]([C:25]2[CH:24]=[CH:23][C:22]([C:20]3[NH:19][C:15]4[N:16]=[CH:17][N:18]=[C:13]([O:12][C:11]5[C:3]([F:2])=[C:4]6[C:8](=[CH:9][CH:10]=5)[NH:7][C:6]([CH3:31])=[CH:5]6)[C:14]=4[CH:21]=3)=[CH:30][CH:29]=2)=[O:28])[CH2:36][CH2:35]1)[CH3:33]
Reactant: Cc1cc2c(F)c(Oc3ncnc4[nH]c(-c5ccc(C(=O)[O-])cc5)cc34)ccc2[nH]1
Reactant: CCN1CCNCC1
Agent: CCOP(=O)(C#N)OCC
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN1CCN(C(=O)c2ccc(-c3cc4c(Oc5ccc6[nH]c(C)cc6c5F)ncnc4[nH]3)cc2)CC1
Reaction time: 1 h

Procedure:
To 340 mg (0.83 mMol) 4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoic acid lithium salt in 5 ml of DMF under N2-atmosphere, 0.38 ml (3 mMol) of N-ethylpiperazine and 0.31 ml (95%; 2 mMol) of diethyl-cyanphosphonate are added at 0° C. After 60 min, the suspension is diluted with EtOAc and washed with saturated NaHCO3-solution, water and brine. The aqueous layers are re-extracted twice with EtOAc, the organic layers dried (Na2SO4) and concentrated after adding SiO2. The resulting powder is put on top of a chromatography column (SiO2) and the title compound eluted with EtOAc/methanol/NH3conc. 80:20:1; HPLC (conditions see Examples 67-78) tR=10.4 min; MS-ES+: (M+H)+=499.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][C:22]1([CH3:34])[CH2:28][CH2:27][CH2:26][O:25][C:24]2[C:29]([NH2:33])=[CH:30][CH:31]=[CH:32][C:23]1=2>>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)=[N:7][C:2]([NH:33][C:29]2[C:24]3[O:25][CH2:26][CH2:27][CH2:28][C:22]([CH3:34])([CH3:21])[C:23]=3[CH:32]=[CH:31][CH:30]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCCOc2c(N)cccc21
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Product: CC1(C)CCCOc2c(Nc3ncc(Cl)c(Nc4ccccc4-n4cccn4)n3)cccc21

Procedure:
The title compound was prepared from (2,5-dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine and 5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine in an analogous manner to Example 179 heating at 140° C. Product was isolated as a white solid (46 mg, 52%). LCMS=461 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.61 (s, 1H), 8.28 (s, 1H), 8.24 (s, 1H), 8.16 (d, 1H, J=7.83 Hz), 7.86 (s, 1H), 7.76 (d, 1H, J=7.58 Hz), 7.66 (d, 1H, J=7.83 Hz), 7.41 (m, 2H), 6.98 (d, 1H, J=8.09 Hz), 6.88 (t, 1H, J=8.33 Hz), 6.56 (s, 1H), 3.92 (m, 2H), 1.69 (m, 2H), 1.61 (m, 2H), 1.32 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.Cl[C:17]([O:19][CH2:20][CH:21]([O:23][CH3:24])[CH3:22])=[O:18]>O1CCCC1>[CH3:24][O:23][CH:21]([CH3:22])[CH2:20][O:19][C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:18]
Reactant: COC(C)COC(=O)Cl
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: C1CCOC1
Product: COC(C)COC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Temperature: 60 °C
Yield: 72.6 %

Procedure:
5.0 g (24.6 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are dissolved in 150 ml of absolute tetrahydrofuran by heating to 60° C., with stirring. The solution is allowed to cool to room temperature, 5.6 g (36.7 millimoles) of 2-methoxypropyl chloroformate are added and the mixture is then stirred for 14 hours under reflux. It is concentrated, water is added and the product is filtered off and recrystallized from dimethylformamide/water, giving 5.7 g (73% of theory) of 4,5-dihydro-6-[p-(2-methoxypropoxycarbonylamino)-phenyl]-5-methyl-3(2H)-pyridazinone as colorless crystals of melting point 173°-175° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[C:9]([CH2:14][S:15][C:16]3[NH:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[N:10]=[CH:11][CH:12]=2)[S:7][CH:6]=1)=[O:4].C1C=C(Cl)C=C(C(OO)=[O:33])C=1.S([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[C:3]([C:5]1[C:13]2[C:8](=[C:9]([CH2:14][S:15]([C:16]3[NH:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[O:33])[N:10]=[CH:11][CH:12]=2)[S:7][CH:6]=1)([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1csc2c(CSc3nc4ccccc4[nH]3)nccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1csc2c(CS(=O)c3nc4ccccc4[nH]3)nccc12
Temperature: 0 °C

Procedure:
To a solution of 140 mg (0.433 mmol) of 2-[(3-methoxycarbonylthieno[2, 3-c]pyridin-7-yl)methylthio]benzimidazole (Ia-10) in 6 ml of CHCl3 and 2 ml of MeOH was added 94 mg (1.1 equivalents) of 80% m-CPBA in the ice-water bath of -10° C., and the mixture was allowed to react for 1 hr. at -10° C. The solution was treated with 10 % aqueous sodium sulfite and saturated aqueous NaHCO3 and extracted with CH2Cl2. The extract was subjected to silica gel column chromatography, eluting with CH2Cl2 --MeOH, and the eluate gave 122 mg (Yield : 75.8%) of 2-[(3-carbomethoxythieno[2, 3-c]pyridin-7-yl)methylsulfinylbenzimidazole (Ic-22) as a foamy product.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([CH2:12][S:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:15])=[O:14])[C:9](O)=[O:10])[CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:44][CH2:45][C:46]#[N:47].CN1CCOCC1>>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([CH2:12][S:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:15])=[O:14])[C:9]([NH:47][CH2:46][C:45]#[N:44])=[O:10])[CH:2]=1
Reactant: O=C(O)C(Cc1cccc(-c2ccccc2)c1)CS(=O)(=O)Cc1ccccc1
Reactant: N#CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: N#CCNC(=O)C(Cc1cccc(-c2ccccc2)c1)CS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Biphenyl-3-yl-2-benzylsulfonylmethyl-propionic acid (300 mg, 0.76 mmol), prepared as in Reference 9, was combined with EDC (300 mg, 1.57 mmol), HOBt (300 mg, 1.96 mmol), and aminoacetonitrile hydrochloride (150 mg, 1.6 mmol). Dichloromethyl (4 mL) was added and then 4-methylmorpholine (0.5 mL). The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (150 mL), the solution was washed with water (30 mL), saturated aqueous NaHCO3 solution and brine, dried with magnesium sulfate and evaporated under vacuum. The product, 3-biphenyl-3-yl-N-cyanomethyl-2-benzylsulfonylmethyl-propionamide (273 mg), was crystallized from ethyl acetate/hexane as a white solid; 1H NMR: (DMSO) 8.87 (t, J=5.5 Hz, 1H), 7.68–7.14 (m, 14H), 4.45 (d, J=13.8 Hz, 1H), 4.38 (d, J=13.8 Hz, 1H), 4.13 (m, 2H), 3.49 (dd, J=9.4 Hz, J=14.1 Hz, 1H), 3.28–3.11 (m, 1H), 3.04–2.76 (m, 3H). MS: (M++1) 433.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[NH:4][C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].Br[CH2:21][C:22]1[N:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:26][CH:27]=1.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH2:21][C:22]2[N:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:26][CH:27]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)[nH]1
Reactant: CCOC(=O)c1cnc(CBr)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)cn1
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
To a mixture of 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (0.59 g, 2.07 mmol) and ethyl 5-(bromomethyl)pyrazine-2-carboxylate (0.62 g, 2.4 mmol) in THF (15 mL) was added NaH (0.06 g, 2.4 mmol). The reaction stirred at 60° C. for 3.5 hours. The solvent was removed under reduced pressure and the residue was partitioned over dichloromethane and citric acid (5%). The organic extracts were washed with water and dried over Na2SO4 (anhydrous). The organic extracts were concentrated and the residue was purified by flash column chromatography (100% ethyl acetate). The appropriate fractions were combined and concentrated under reduced pressure to remove solvent. 1H NMR (CD3OD, 400 MHz) δ 9.11 (d, 1H, J=1.6 Hz), 8.77 (s, 1H), 7.52 (m, 1H), 7.02 (m, 2H), 6.57 (s, 1H), 5.53 (s, 2H), 5.30 (s, 2H), 4.49 (q, 2H), 2.52 (s, 3H), 1.39 (t, 3H, J=7.2 Hz); ES-HRMS m/z 450.1045 (M+H calculated for C21H19N3O4ClF2 requires 450.01027).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5](I)=[CH:4][N:3]=1.[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11]>C1COCC1.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.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:11]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1ncc(I)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cnc(Cl)nc1Cl
Temperature: 35 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
Under nitrogen atmosphere, a mixture of 2,4-dichloro-5-iodopyrimidine (2.0 g, 7.3 mmol, 1.0 eq), Pd(PPh3)2Cl2 (256 mg, 0.37 mmol, 0.05 eq), CuI (139 mg, 0.73 mmol, 0.1 eq) Et3N (2.2 g, 21.9 mmol, 3.0 eq) and ethynyltrimethylsilane (1.4 g, 14.6 mmol, 1.2 eq) in THF (20 ml) was stirred at 35° C. for 4 h. The mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc=200:1) to give compound 2,4-dichloro-5-((trimethylsilyl)ethynyl)pyrimidine (1.0 g, 56%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1.[CH3:13][NH2:14]>CO>[CH3:13][NH:14][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1
Reactant: CN
Reactant: Cc1ccc(OCCCCl)cn1
Solvent: CO
Product: CNCCCOc1ccc(C)nc1
Temperature: 100 °C
Yield: 45.3 %

Procedure:
The 3-chloro-1-(6-methyl(3-pyridyloxy))propane (2.78 g, 18.3 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (25 mL) was added to the residue. The pH was adjusted to 1 with 100% HCl solution and impurities were extracted with chloroform (4×25 mL). The pH of the aqueous phase was raised to 7 with 100% NaOH solution and other impurities were extracted with ether (4×30 mL). The aqueous layer was basified to pH 11 with 100% NaOH solution and extracted with ether (4×50 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 1.224 g (45.3%) of an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>O1CCCC1>[C:21]([N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCN(Cc2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
A solution of 1-benzylpiperazine (1 g) and triethylamine (1.19 mL) in tetrahydrofuran (20 mL) was stirred at room temperature under argon. Acetyl chloride (0.424 mL) was added and the mixture was stirred for 10 minutes. The reaction was filtered and the white solid washed with ether. The filtrate was concentrated at reduced pressure to give the title compound as a colourless oil (1.2 g).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]2=[O:18])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([CH:45]=[CH:46][CH:47]=2)[O:36][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)O1>O1CCOCC1.O>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]2=[CH:7][C:5]1[O:6][C:2]([C:46]2[CH:47]=[CH:33][CH:34]=[C:35]([O:36][CH2:37][CH2:38][N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)[CH:45]=2)=[CH:3][CH:4]=1
Reactant: CC1(C)OB(c2cccc(OCCN3CCOCC3)c2)OC1(C)C
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(Br)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(-c2cccc(OCCN3CCOCC3)c2)o1
Temperature: 120 °C

Procedure:
To 3-((5-bromofuran-2-yl)methylene)-5-chloroindolin-2-one (50 mg, 0.155 mmol) in dioxane/water (5% water) was added Cs2CO3 (152 mg, 0.466 mmol) and 4-(2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)morpholine (62 mg, 0.186 mmol). The mixture was degassed with nitrogen for 5 minutes then heated in microwave for 20 minutes at 120° C. The solution was diluted with water and the solid formed was isolated by filtration. The solid was purified by HPLC to yield 5-chloro-3-((5-(3-(2-morpholinoethoxy)phenyl)furan-2-yl)methylene)indolin-2-one. LCMS (M+1=451).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:19])=[N-]>C1COCC1>[OH:13][C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:14]([O:16][CH3:19])=[O:15])[CH2:10]1
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Yield: 96.1 %

Procedure:
To a solution of compound 235 (5.2 g, 22.49 mmol) in THF (50 mL) was added diazomethane (38.5 mL, 27.0 mmol, 0.7M) dropwise until yellow color persists. The mixture was concentrated to afford title compound 236 (5.3 g, 96%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ (ppm): 4.50-4.47 (m, 1H), 4.44 (t, J=7.7 Hz, 1H), 3.76-3.43 (m, 2H), 3.73 (s, 3H), 2.33-2.22 (m, 1H), 2.11-2.03 (m, 1H), 1.91 (m, 1H), 1.45-1.41 (m, 9H). LRMS (ESI): (calc.) 245.13 (found) 146.0 (M-Boc+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9](=[O:10])[NH:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCc1ccc(CN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NCc1ccc(CNC(=O)OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
A solution of benzylchloroformate (10.48 ml, 74 mmol) in dichloromethane (250 ml) was added to an ice-cooled solution of 4-aminomethyl benzylamine (10 g, 74 mmol) and triethylamine (9.77 ml, 74 mmol), in dichloromethane (480 ml) over 90 minutes. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (450 ml) and 1M sodium hydroxide solution (300 ml). The resulting mixture was filtered, the layers separated and the organic phase dried over magnesium sulphate and evaporated under reduced pressure. The residue was dissolved in hot ethyl acetate, the solution cooled in an ice-bath, the resulting solid filtered off, and the filtrate evaporated under reduced pressure to afford the title compound as a white solid, 7.44 g.
Reaction SMILES: [CH3:1][C:2]1([OH:18])[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:4][CH2:3]1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:5]1[CH2:6][CH2:7][CH2:8][C:2]([CH3:1])([OH:18])[CH2:3][CH2:4]1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCCC(C)(O)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cn1ncc(N)c1N1CCCC(C)(O)CC1
Temperature: 80 °C

Procedure:
To a solution of 4-methyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ol (212 mg, 0.83 mmol) and ammonium formate (386 mg, 6.6 mmol) in MeOH (15 mL) under nitrogen was added 10% palladium on carbon (88 mg, 0.83 mmol). The mixture was heated at 80° C. for 16 hr before being cooled, filtered through Celite® and concentrated under reduced pressure. The residue was partitioned between water (20 mL) and DCM (40 mL) and the organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure to give 1-(4-amino-1-methyl-1H-pyrazol-5-yl)-4-methylazepan-4-ol as a red oil which was used without further purification. To a solution of DIPEA (0.06 mL, 0.33 mmol), PyBOP (151 mg, 0.29 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (89 mg, 0.25 mmol) in DCM (10 mL) (pre-stirred for 30 min) was added 1-(4-amino-1-methyl-1H-pyrazol-5-yl)-4-methylazepan-4-ol (47 mg, 0.21 mmol) and the mixture was stirred at room temperature for 16 hr. The mixture was diluted with DCM (30 mL) and water (20 mL). The organic layer was passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(5-(4-hydroxy-4-methylazepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as an off-white solid (109 mg). This solid was stirred with HCl in 1,4-dioxane (4 M, 5 mL, 20 mmol) in MeOH (5 mL) at room temperature for 16 h. The solvent was removed under reduced pressure, the residue re-dissolved in MeOH and passed through an SCX column, washing with DCM and MeOH and eluting with 3-10% 7 N ammonia in MeOH/DCM. Purification via silica gel column chromatography (0-5% MeOH/DCM) gave 146 as an off-white solid (36 mg, 37% over 3 steps). 1H NMR (400 MHz, d4-MeOD) δ 7.68 (s, 1H), 7.52-7.43 (m, 1H), 7.17-7.10 (m, 2H), 3.74 (s, 3H), 3.56-3.44 (m, 1H), 3.19-3.10 (m, 1H), 3.04-2.96 (m, 1H), 2.14-2.02 (m, 1H), 1.94-1.80 (m, 4H), 1.74-1.64 (m, 1H), 1.23 (s, 3H) (1 proton coincident with solvent peak). LCMS (ES+) m/z 463 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=1.[C:19]1([CH:25]2[N:29]([C:30]3[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=3)[N:28]=[C:27]([C:38]3[C:51]4[C:52]5=[C:53]6[C:48](=[CH:49][CH:50]=4)[CH:47]=[CH:46][CH:45]=[C:44]6[CH:43]=[CH:42][C:41]5=[CH:40][CH:39]=3)[CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1CCCCC1>C(O)C>[C:13]1([C:4]2[O:3][C:2]([CH:1]=[CH:34][C:33]3[CH:36]=[CH:37][C:30]([N:29]4[CH:25]([C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:26][C:27]([C:38]5[C:51]6[C:52]7=[C:53]8[C:48](=[CH:49][CH:50]=6)[CH:47]=[CH:46][CH:45]=[C:44]8[CH:43]=[CH:42][C:41]7=[CH:40][CH:39]=5)=[N:28]4)=[CH:31][CH:32]=3)=[CH:7][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:5]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1=CC(=C(C#N)C#N)C=C(c2ccccc2)O1
Reactant: O=Cc1ccc(N2N=C(c3ccc4ccc5cccc6ccc3c4c56)CC2c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(C#N)=C1C=C(C=Cc2ccc(N3N=C(c4ccc5ccc6cccc7ccc4c5c67)CC3c3ccccc3)cc2)OC(c2ccccc2)=C1
Temperature: 75 °C

Procedure:
As shown in the following reaction 8, 0.24 g (1.0 mmol) of 2-(2-methyl-6-phenyl-pyran-4-ylidene)-malononitrile and 0.46 g (1.0 mmol) of 4-(5-phenyl-3-pyren-1-yl-4,5-dihydro-pyrazol-1-yl)benzaldehyde were added into 20 ml of ethanol, and 0.13 g (1.53 mmol) of piperidine was added thereto. The reaction solution was heated at 75° C. for 10 hours.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([I:9])=[CH:4][N:3]=1.[NH2:10][CH2:11][CH2:12][OH:13]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:5]([I:9])=[CH:4][N:3]=1
Reactant: NCCO
Reactant: Clc1ncc(I)c(Cl)n1
Product: OCCNc1nc(Cl)ncc1I
Yield: 83 %

Procedure:
In analogy to GP 2, reaction of 2,4-dichloro-5-iodopyrimidine (2.0 g, 7.3 mmol) with 2-amino-ethanol (480 mg, 7.9 mmol) provided the desired product in 83% yield (1.8 g) after chromatographic purification (silica gel, dichloromethane/methanol (0% to 20% methanol)).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)[N:3]=1.CN.[CH:22]([N:25](C(C)C)CC)(C)C>ClCCl>[Cl:8][C:6]1[N:7]=[C:2]([NH:25][CH3:22])[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)[N:5]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)C1CCN(c2nc(Cl)nc(Cl)n2)CC1
Agent: CN
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2nc(Cl)nc(NC)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a solution of ethyl 1-(4,6-dichloro-1,3,5-triazin-2-yl)-4-piperidinecarboxylate (1.0 g, 3.3 mmol, 1.0 equiv) in dichloromethane (20 ml) at room temperature, a premixed solution of methylamine (1.6 ml, 3.3 mmol, 1.0 equiv) and diisopropylethylamine (DIEA, 1.7 ml, 9.8 mmol, 3.0 equiv) in dichloromethane (10 ml) was added dropwise. The reaction was stirred for 3 h at room temperature. The solvent was removed under reduced pressure to afford 983 mg (100%) of the title compound. MS (ES+): m/e 300.1 [M+H]+.