Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=3)=[O:13])[CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Na+].Cl>C(O)C>[S:1]1[C:7]2[CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=3)=[O:13])[CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)SCCCC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)SCCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
1.20 g of ethyl p-(2,3,4,5-tetrahydro-1-benzothiepine-8-carboxamido)benzoate were dissolved in 40 ml of ethanol and treated with 14 ml of water containing 1.40 g of NaOH. The mixture was stirred at room temperature overnight, poured on to ice and acidified with conc. HCl. The mixture was then extracted twice with ethyl acetate, washed with water, dried and evaporated. Recrystallization from ethyl acetate gave 925 mg of p-(2,3,4,5-tetrahydro-1-benzothiepine-8-carboxamido)benzoic acid as colorless crystals of m.p. 261°-262° C.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C:15]2[CH:27]=[CH:26][C:18]([C:19](C(OCC)=O)=O)=[CH:17][CH:16]=2)C=CC=CC=1.[OH:28][C:29]1[C:30](=[O:42])[O:31][C:32]([CH3:41])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:33]=1[OH:34]>C1COCC1>[C:38]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:39]=[CH:40][C:35]([C:32]2([C:41]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)[O:31][C:30](=[O:42])[C:29]([O:28][CH2:19][C:18]3[CH:17]=[CH:16][CH:15]=[CH:27][CH:26]=3)=[C:33]2[OH:34])=[CH:36][CH:37]=1
Reactant: CC1(c2ccccc2)OC(=O)C(O)=C1O
Reactant: CCOC(=O)C(=O)c1ccc(-c2ccccc2)cc1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=C1OC(c2ccccc2)(c2ccc(-c3ccccc3)cc2)C(O)=C1OCc1ccccc1
Yield: 20 %

Procedure:
A total of 3.4 mL (10.2 mmol) of 3.0M phenylmagnesium bromide was added to a solution of 2.4 g (10 mmol) of ethyl 4-phenylbenzoylformate in THF in an analogous manner as described for the synthesis of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to give prior to hydrogenolysis 0.88 g (20% yield) of 5-[(1,1′-biphenyl)-4-yl]-4-hydroxy-3-phenylmethoxy-5-phenyl-2(5H)-furanone as an off white solid: mp 190-195° C. (CHCl2/hexanes).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[Cl:8][C:9]1[CH:10]=[C:11]([NH:15][NH2:16])[CH:12]=[CH:13][CH:14]=1.Br[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].[CH2:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([N:15]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][CH2:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:16]2)[CH:12]=[CH:13][CH:14]=1
Reactant: C=Cc1ccccc1
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)C(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=NN(c2cccc(Cl)c2)C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.3 %

Procedure:
To 12.0 g (0.112 mol) of sodium carbonate suspended in 50 mL THF was added 5.0 g (0.028 mol) 3-chlorophenyl hydrazine hydrochloride, 6.5 g (0.033 mol) ethyl bromopyruvate and 44.0 g (0.42 mol) styrene. The reaction mixture was stirred at room temperature for 18 h, filtered through a plug of celite, rinsed with methylene chloride and concentrated under reduced pressure. The crude reaction mixture was flash chromatographed using 10% EtOAc/90% hexanes as eluent to afford 3.2 g of a yellow solid, mp 125°-126° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3C(=O)C4=CC=CC=C4C3=O)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O.NN>C(O)C>[NH2:20][CH2:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:18]=1
Reactant: COc1cc(-c2cc(CN3C(=O)c4ccccc4C3=O)ccn2)cc(OC)c1OC
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(-c2cc(CN)ccn2)cc(OC)c1OC

Procedure:
To a suspension of N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]phthalimide (1.16 g) in ethanol (30 mL) was added hydrazine monohydrate (1 mL). The mixture was refluxed for 3 hours. After cooling, the precipitates were filtered off. The filtrate was evaporated and the residue was dissolved in chloroform. The solution was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and evaporated to give the title compound as pale yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:22])[C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([Br:19])[C:12]=1[O:20]C)[CH3:2].B(Br)(Br)Br.C(Cl)[Cl:28]>>[ClH:28].[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:22])[C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([Br:19])[C:12]=1[OH:20])[CH3:2]
Reactant: ClCCl
Reactant: CCN1CCCC1CNC(=O)c1c(OC)ccc(Br)c1OC
Agent: BrB(Br)Br
Product: CCN1CCCC1CNC(=O)c1c(OC)ccc(Br)c1O
Product: Cl

Procedure:
10.0 g (0.025 ml) of (-)-N-ethyl-2-(3-bromo-2,6-dimethoxybenzamidomethyl)pyrrolidine is dissolved in 250 ml of methylene chloride. 2.6 ml (0.027 mol) of boron tribromide is added. The mixture is left over night at room temperature. It is then washed with 2N NH3, dried over Na2SO4 and evaporated after addition of HCl-ether. The residue is dissolved in water and extracted with ether. The water phase is made alkaline with NH3 and is extracted with chloroform. The chloroform phase is dried over Na2SO4 and evaporated. To the residue is added HCl-ether. The salt is filtered off, washed with ether and dried over P2O5. M.p.: sinterring at 100° C. Yield 6.6 g. Hygroscopic [α]D20 =-45.5° (base).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=1[Cl:18])[N:5]=2.[Cl:33][CH2:34][C:35](Cl)=[O:36]>CN(C)C(=O)C.C(OCC)(=O)C>[Cl:18][C:17]1[CH:16]=[CH:15][C:14]([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:28])[CH3:29])[CH:22]=2)=[CH:13][C:12]=1[O:11][C:6]1[N:5]=[C:4]2[S:3][C:2]([NH:1][C:35](=[O:36])[CH2:34][Cl:33])=[N:10][C:9]2=[CH:8][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Cl)c(Oc3ccc4nc(N)sc4n3)c2)c1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Cl)c(Oc3ccc4nc(NC(=O)CCl)sc4n3)c2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chlorophenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.431 mmol) produced in Example C50(v) in N,N-dimethylacetamide (3.0 mL) was added chloroacetyl chloride (75.4 μL, 0.948 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate (20 mL), washed with 5% aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give N-[4-chloro-3-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)phenyl]-3-(1-cyano-1-methylethyl)benzamide as an oily residue.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[CH2:14][CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCOc1cccc(OC(F)(F)F)c1
Temperature: 80 °C
Yield: 80.6 %

Procedure:
To a solution of 3-(trifluoromethoxy)phenol (0.3 g, 1.68 mmol) in DMF (10 mL) was added 3-bromopropan-1-ol (0.47 g, 3.37 mmol) and potassium carbonate (0.47 g, 3.37 mmol). The reaction was heated at 80° C. overnight. The mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether and ethyl acetate (10:1) to give 3-(3-(trifluoromethoxy)phenoxy)propan-1-ol (0.32 g, 80.6% yield) as yellow oil.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]([F:17])([F:16])[C:6]1[CH:7]=[C:8]([CH2:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1.[Cl-].[NH4+]>C(OCC)C.C1COCC1>[CH3:14][C:13]([OH:15])([CH3:1])[CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:5]([F:16])([F:17])[F:4])[CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(=O)Cc1cccc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)Cc1cccc(C(F)(F)F)c1
Temperature: -50 °C
Reaction time: 8 h

Procedure:
90 mL of a 3 molar solution of methylmagnesium bromide in diethyl ether are diluted with 300 mL THF and cooled to −50° C. At this temperature 20 g 1-(3-trifluoromethyl-phenyl)-propan-2-one, dissolved in 100 mL THF, are added dropwise. After the addition has ended the reaction mixture is stirred overnight while heating to ambient temperature. It is combined with ammonium chloride solution and extracted with diethyl ether. The combined organic phases are washed with sodium chloride solution, dried with sodium sulphate and evaporated down. The residue remaining is purified by chromatography.
Reaction SMILES: O1C2(C[CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:32]#[N:33])=[CH:27][C:28]([F:31])=[CH:29][CH:30]=5)=[CH:21][CH:20]=4)=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]4[N:37]=[C:38]([CH3:40])[N:39]=[C:12]34)[CH2:7][CH2:6]2)OCC1.Cl.O1CC[CH2:44][CH2:43]1.[C:47]([O:50][CH2:51][CH3:52])(=[O:49])[CH3:48]>>[CH3:52][CH:51]1[CH:43]([CH3:44])[O:49][C:47]2([CH2:6][CH2:7][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]5[C:26]([C:32]#[N:33])=[CH:27][C:28]([F:31])=[CH:29][CH:30]=5)=[CH:23][CH:24]=4)=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]4[N:37]=[C:38]([CH3:40])[N:39]=[C:12]34)[CH2:9][CH2:48]2)[O:50]1
Reactant: CCCc1c(Cc2ccc(-c3ccc(F)cc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Reactant: C1CCOC1
Reactant: CCOC(C)=O
Agent: Cl
Product: CCCc1c(Cc2ccc(-c3ccc(F)cc3C#N)cc2)c(=O)n(C2CCC3(CC2)OC(C)C(C)O3)c2nc(C)nn12
Temperature: 70 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-4-fluorobiphenyl-2-carbonitrile (1.1 g), 3N hydrochloric acid (30 mL) and tetrahydrofuran (30 mL) was stirred at 70° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in toluene (30 mL), 2,3-dimethylpropane-1,3-diol (0.2 g) and p-toluenesulfonic acid monohydrate (0.004 g) were added, and the mixture was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 3 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.3 g, 100%).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:22])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH2:23][CH2:24][CH2:25][CH2:26][OH:27].[CH3:28][CH2:29][N:30]([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32]>CC(O)C>[Br:1][C:2]1[C:3]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][CH2:29][N:30]([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32].[ClH:22]
Reactant: NCCCO
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(NCCCO)c(Br)c1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 198 mg, 0.50 mmol), 3-aminopropan-1-ol (45 mg, 0.60 mmol), iPrOH (2 mL) and DIPEA (0.171 mL, 0.129 g, 1.0 mmol) were subjected to MW irradiation at 140° C. for 150 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure. No further purification was required to afford the title compound as an equimolar mixture with DIPEA hydrochloride. UPLC-MS (Condition 8) tR=1.46 min, m/z=434.0 [M+H]+, m/z=432.1 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:21]/[NH:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)/[CH3:9])[CH:7]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1ccccc1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 53.2 %

Procedure:
1-(5-Chloro-2-hydroxyphenyl)ethanone (100 mg, 0.586 mmol) and benzohydrazide (80 mg, 0.586 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound (90 mg) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 7.95 (m, 2H), 7.67-7.62 (m, 2H), 7.56 (m, 2H), 7.35 (dd, 1H, J=2.4 & 8.8 Hz), 6.95 (d, 1H, J=8.4 Hz), 3.35 (s, 3H). ESI-MS: 289.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:32][CH2:33][C:34](Cl)=[O:35])[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29].[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl.CCOC(C)=O>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([CH2:32][CH2:33][C:34]([C:10]2[C:11]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:12]=3[S:13][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:35])[CH:23]=[C:22]([O:21][CH3:20])[C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: COc1cc(CCC(=O)Cl)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)CCc2cc(OC)c(OC)c(OC)c2)cc1

Procedure:
To a well-stirred solution of 2-(4'-methoxyphenyl)-6-methoxybenzo[b]thiophene (0.206 g, 0.762 mmol) and 3-(3',4',5'-trimethoxyphenyl)propionyl chloride (0.390 g, 1.51 mmol) in CH2Cl2 (50 mL) was added AlCl3 (0.520 g, 3.89 mmol) portion-wise over a 15 minute period. After 18 hours (total reaction time), water was added, and the product was isolated initially by extraction with CH2Cl2 and subsequently by extraction with EtOAc. The organic layers were separately washed sequentially with NaHCO3 (sat) and brine and then combined and dried over MgSO4. Purification by flash chromatography (silica gel, 70:30 EtOAc/hexane) afforded the title compound as an off-white solid. 1H-NMR (CDCl3, 360 Mhz): δ=7.92 (d,J=8.9 Hz, 1H, ArH), 7.35 (d,J=8.7 Hz, 2H, ArH), 7.25 (m,1H, ArH), 7.04 (dd,J=8.9,2.4 Hz, 1H, ArH), 6.93 (d,J=8.7 Hz, 2H, ArH), 6.15 (s,2H, ArH) 3.88 (s,3H, --OCH3), 3.85 ((s,3H, --OCH3), 3.78 (s, 3H, --OCH3), 3.72 (s,6H, --OCH3), 3.80 (t,2H, CH2), 3.70 (t,2H, CH2).
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)[CH2:2][CH3:3].[Cl:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13]>CO>[Cl-:9].[OH:14][CH:11]([CH2:12][OH:13])[CH2:10][N+:6]1[CH:7]=[CH:8][N:4]([CH2:1][CH2:2][CH3:3])[CH:5]=1
Reactant: CCCn1ccnc1
Reactant: OCC(O)CCl
Solvent: CO
Product: CCCn1cc[n+](CC(O)CO)c1
Product: [Cl-]
Reaction time: 48 h
Yield: 94.2 %

Procedure:
1-Propylimidazole (2.75 g, 25.0 mmol) and 3-chloro-1,2-propanediol (2.76 g, 25.0 mmol) were stirred in a 130° C. oil bath for 48 h, after which the flask was placed under vacuum and stirring continued at 130° C. for another 48 h. The residue was then dissolved in CH3OH, transferred to a tared flask and concentrated to afford the product as a viscous brown oil (5.20 g, 95%). 1H NMR: δH ppm (400 MHz; DMSO-d6) 0.84 (t, J=7.42 Hz, 3H) 1.74-1.86 (m, 2H) 3.22 (dd, J=11.17, 6.96 Hz, 1H) 3.42 (dd, J=10.99, 4.95 Hz, 1H) 4.07-4.20 (m, 3H) 4.33 (dd, J=13.74, 3.11 Hz, 1H) 5.15 (br. s., 1H) 5.56 (br. s., 1H) 7.78 (t, J=1.74 Hz, 1H) 7.82 (t, J=1.83 Hz, 1H) 9.29 (t, J=1.47 Hz, 1H).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](Cl)=[O:34])=[CH:28][CH:27]=1)([O-:25])=[O:24]>C(Cl)Cl>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[O:34])=[CH:30][CH:31]=1)([O-:25])=[O:24]
Reactant: NCCN1CCN(c2ccccc2)CC1
Reactant: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)NCCN1CCN(c2ccccc2)CC1
Reaction time: 2 h
Yield: 89 %

Procedure:
To a stirred solution of 2-(4-Phenyl-piperazin-1-yl)-ethylamine 4a (0.5 g, 2.44 mmol) and Et3N (0.34 g, 3.41 mmol) in 40 mL of dry CH2Cl2 under nitrogen at 0° C. was added a solution (4-Nitro-phenyl)-acetyl chloride (0.58 g, 2.92 mmol). The temperature was allowed to rise to room temperature, the mixture was stirred for 2 h, and then washed with water. The aqueous layer was extracted with dichloromethane. The combined organic phase was washed with saturated sodium chloride, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography over silica gel (EtOAc) to produce 26a: 0.8 g, (89% yield) as a white solid (mp: 138-139° C.). 1H NMR (CDCl3, 400 MHz): δ2.52 (2H, t, J=5.6, CH2—CH2NH), 2.57 (4H, t, J=5.2, (CH2)2N—), 3.11 (4H, t, J=5.2, (CH2)2—NPh), 3.36−3.34 (2H, m, CH2—NHCO), 3.65 (2H, s, CH2Ar), 6.19 (1H, bs, NHCO), 6.86-6.91(3H, m, ArH), 7.25-7.29 (2H, m, ArH), 7.47 (2H, d, J=8.8, ArH), 8.16-8.19 (2H, m, ArH).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:32][CH2:33]3)[S:26][CH:27]=2)=[CH:19][CH:18]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: Fc1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3ccc(F)cc3)cs2)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 68.3 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (225 mg, 0.835 mmol), 1-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 18 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give the desired product (199 mg, 68.5%) as a solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12]4[CH:19]=[C:18](I)[NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:21][O:22][CH2:23][CH2:24][N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][C:26]1=[O:34].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12]4[CH:19]=[C:18]([C:28]5[CH:29]=[CH:30][N:25]([CH2:24][CH2:23][O:22][CH3:21])[C:26](=[O:34])[CH:27]=5)[NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COCCn1ccc(B(O)O)cc1=O
Reactant: Ic1cc2c(Nc3ccc4[nH]ncc4c3)ncnc2[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COCCn1ccc(-c2cc3c(Nc4ccc5[nH]ncc5c4)ncnc3[nH]2)cc1=O
Temperature: 100 °C

Procedure:
A mixture of (1H-indazol-5-yl)-(6-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (0.076 g), 1-(2-methoxy-ethyl)-2-oxo-1,2-dihydro-pyridine-4-boronic acid (36 mg), PdCl2(PPh3)2 (7 mg) end potassium carbonate (76 mg) in dioxane/wawr (4:1) (5 mL) was heated to 100° C. for 48 h. Purification via chromatograpby afforded tJm title compound as a pale yellow solid. δH 3.30 (3H, s), 3.62 (2H, t), 4.18 (2H, t), 5.99 (1H, dd), 6.89 (1H, d), (7.27 (1H, s), 7.57 (2H, d), 7.69 (2H, m), 8.09 (1H, s), 8.16 (1H, s), 8.18 (1H, s) and 9.67 (1H, s). MH+ 402.13.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:18]=[CH:19][C:20]2[C:30]3[C:25](=[C:26]([NH:31][C:32](=[O:34])[CH3:33])[N:27]=[CH:28][CH:29]=3)[CH:24]([CH3:35])[O:23][C:21]=2[CH:22]=1>>[C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:9][O:10][C:17]1[CH:18]=[CH:19][C:20]2[C:30]3[C:25](=[C:26]([NH:31][C:32](=[O:34])[CH3:33])[N:27]=[CH:28][CH:29]=3)[CH:24]([CH3:35])[O:23][C:21]=2[CH:22]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(=O)Nc1nccc2c1C(C)Oc1cc(Cl)ccc1-2
Product: CC(=O)Nc1nccc2c1C(C)Oc1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc1-2
Yield: 51 %

Procedure:
Prepared as described in Example 8, Part C using (S)-tert-butyl(1-hydroxy-4-methylpentan-2-yl)carbamate and N-(8-chloro-5-methyl-5H-chromeno[3,4-c]pyridin-4-yl)acetamide to afford tert-butyl((2S)-1-((4-acetamido-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.6 g, 0.882 mmol, 51% yield) as a yellow solid. LCMS (ESI) m/e 470.2 [(M+H)+, calcd for C26H36N3O5 470.3]; LC/MS retention time (Method C): tR=1.89 min.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](=[S:28])[NH2:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:30][C:31](=O)[CH3:32]>>[CH3:32][C:31]1[N:27]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:28][CH:30]=1
Reactant: CC(=O)CCl
Reactant: NC(=S)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: Cc1csc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
100 mg (about 0.182 mmol) of the compound from Example 115A and 25 mg (0.273 mmol) of 1-chloropropan-2-one were reacted according to the General Method 3. Yield: 40 mg (44% of theory).