Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[CH2:16]([N:18](CC)CC)[CH3:17].C(N)C>C1COCC1>[CH2:16]([NH:18][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1)[CH3:17]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Cl
Agent: CCN
Solvent: C1CCOC1
Product: CCNc1nc(SC)nc(C)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (65 g) in THF (1000 mL) and triethylamine (110 mL, 0.81 mole) was added ethylamine (2.0 M in THF, 0.81 mole) at 0° C. This reaction mixture was stirred at room temperature overnight and then solvents were removed on a rotary evaporator. H2O was added and the mixture extracted with ethyl acetate several times. Solvents from the combined organic layers were removed on a rotary evaporator affording 58 g (86% yield) of ethyl 4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carboxylate. This material was used as such without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[CH3:20])[N:3]=1.[Br:21][C:22]1[CH:23]=[C:24]([Cl:35])[C:25]([N:28]2[CH2:33][CH2:32][NH:31][C@H:30]([CH3:34])[CH2:29]2)=[N:26][CH:27]=1.C([O-])(O)=O.[Na+]>CCO>[Br:21][C:22]1[CH:23]=[C:24]([Cl:35])[C:25]([N:28]2[CH2:33][CH2:32][N:31]([C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=4)[N:5]=[C:4]([N:15]4[CH2:19][CH2:18][CH2:17][C@@H:16]4[CH3:20])[N:3]=3)[C@H:30]([CH3:34])[CH2:29]2)=[N:26][CH:27]=1
Reactant: C[C@H]1CCCN1c1nc(Cl)cc(-c2ccc(F)cc2)n1
Reactant: C[C@@H]1CN(c2ncc(Br)cc2Cl)CCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@@H]1CN(c2ncc(Br)cc2Cl)CCN1c1cc(-c2ccc(F)cc2)nc(N2CCC[C@@H]2C)n1

Procedure:
Heat a mixture of 4-chloro-6-(4-fluoro-phenyl)-2-(2-(S)-methyl-pyrrolidin-1-yl)-pyrimidine (1.30 g, 4.44 mmol), 1-(5-bromo-3-chloro-pyridin-2-yl)-3-(R)-methyl-piperazine (1.2 g), and NaHCO3 (0.71 g, 8.46 mmol) in EtOH at 50° C. for 20 h. Concentrate under reduced pressure and partition between EtOAc and brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc-Hexanes (1:4) to afford the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH:28]=2)[CH:26]=[O:27])O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH:26]=[O:27])[CH:28]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH3:12]
Reactant: CCOc1cc(Br)ccc1C#N
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOc1cc(-c2cncc(C=O)c2)ccc1C#N
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-2-ethoxybenzonitrile (1.13 g, 5.00 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinaldehyde (1.165 g, 5.00 mmol), sodium carbonate (5.00 mL, 10.00 mmol) and Pd(PPh3)4 (1.136 g, 0.125 mmol) in DME (20 mL) was heated to reflux for 6 h. After cooling to room temperature, filtration, drying over Na2SO4, concentration, a colorless solid was obtained. 1H NMR (400 MHz, CDCl3): δ 7.14 (d, J=1.5 Hz, 1H), 7.23 (dd, J=8, 1.5 Hz, 1H), 7.70 (d, J=8=Hz, 1H), 8.33 (t, J=2 Hz, 1H), 9.06 (d, J=2 Hz, 1H), 9.11 (d, J=2 Hz, 1H), 10.21 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]([CH3:11])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16]>>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH:16][C:2]1[C:7]2[N:8]([CH3:11])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: NCc1ccccc1F
Reactant: Cn1cnc2ccnc(Cl)c21
Product: Cn1cnc2ccnc(NCc3ccccc3F)c21

Procedure:
A mixture of 16.76 g of 4-chloro-3-methyl-3H-imidazo(4,5-c)pyridine and 30 g of o-fluorobenzylamine is melted at 180° for 2 hours. After customary working up, 4-o-fluorobenzylamino-3-methyl-3H-imidazo-(4,5-c)pyridine of m.p. 163°-164° is obtained.
Reaction SMILES: C(OC([N:8]([C:24]1[CH:29]=[N:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[CH:26][N:25]=1)[CH:9]([C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:39][C:36]([F:37])([F:38])[C:33]1[CH:34]=[CH:35][C:30]([C:27]2[N:28]=[CH:29][C:24]([NH:8][CH:9]([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][CH:23]=3)[CH2:10][CH2:11][CH3:12])=[N:25][CH:26]=2)=[CH:31][CH:32]=1
Reactant: CCCC(c1ccc(C(=O)OCC)cc1)N(C(=O)OC(C)(C)C)c1cnc(-c2ccc(C(F)(F)F)cc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(Nc1cnc(-c2ccc(C(F)(F)F)cc2)cn1)c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Part A: A round bottom flask was charged with (±)-ethyl 4-(1-((tert-butoxycarbonyl)(5-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)amino)butyl)benzoate (4.85 g, 8.92 mmol), DCM (60 mL) and TFA (15 mL). Reaction mixture stirred at room temperature for 3 hours. Sodium bicarbonate (sat. aq.) used to quench the excess TFA and the aqueous layer is extracted with DCM (3×). Combined organics washed with water (1×), brine (1×), dried over sodium sulfate filtered and concentrated to provide (±)-ethyl 4-(1-((5-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)amino)butyl)benzoate as a crude orange gum (4.01 g, quant.). No further purification before next step. MS (M+1): 444.3.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>C1C=CC=CC=1>[CH2:13]([N:15]([CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1)[CH2:16][CH3:17])[CH3:14]
Reactant: CCNCC
Reactant: CCOC(=O)c1ccc(CCl)o1
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(CN(CC)CC)o1

Procedure:
Ethyl 5-(chloromethyl)-2-furoate (0.1 mole) is refluxed with diethylamine (0.25 mole) in 40 ml of benzene for one hour. The benzene solution is filtered off and washed with water. The organic layer is separated and dried over magnesium sulfate. The magnesium sulfate is removed by filtration and the organics are evaporated to dryness. The residue is distilled to give a pure fraction of ethyl 5-(N,N-diethylaminomethyl)-2-furoate boiling at 97°-106° C. at 0.1 mm of Hg.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:14][CH2:15][CH2:16][C@@H:17]2[CH2:19][C@@H:18]2[CH:20]2[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]2)=[N:4][CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:7]=1.[OH:28][NH:29][C:30](=N)[CH:31]([CH3:33])[CH3:32].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:5]=[N:4][C:3]=1[O:14][CH2:15][CH2:16][C@@H:17]1[CH2:19][C@@H:18]1[CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[O:28][N:29]=[C:30]([CH:31]([CH3:33])[CH3:32])[N:27]=2)[CH2:22][CH2:21]1
Reactant: CC(C)C(=N)NO
Reactant: Cc1cc(N2CCNC2=O)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C#N)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCNC2=O)cnc1OCC[C@@H]1C[C@@H]1C1CCN(c2nc(C(C)C)no2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The mixture of 4-[(1R,2S)-2-(2-{[3-methyl-5-(2-oxoimidazolidin-1-yl)pyridine-2-yl]oxy}ethyl)cyclopropyl]piperidine-1-carbonitrile (13 mg, 0.035 mmol), N-hydroxy-2-methylpropanimidamide (5 mg., 0.05 mmol) and zinc chloride (0.1 mL., 0.05 mmol) in 1 mL of DMF was stirred 2 hrs at 80° C., then PTSA (7 mg, 0.037 mmol) was added and stirred for additional 2 hrs at 85° C. The mixture was cooled to room temperature and then quenched by sat'd aq soln of NaHCO3. The mixture was extracted with EtOAc (2×5 mL), and the combined organics were then washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified Gilson HPLC eluting with a gradient of 10-90% acetonitrile in water with 0.05% TFA as buffer. The fractions containing product were collected into a 20 mL scintillation vial and frozen via a dry ice/acetone bath. The frozen material was then lyophilized overnight to give the product as a white fluffy solid. LCMS (ESI) m/z 455 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([O:25][Si](C(C)(C)C)(C)C)=[C:20]([CH3:33])[CH:19]=2)([OH:17])[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])([C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([OH:25])=[C:20]([CH3:33])[CH:19]=2)[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C2(O)C(=O)N(Cc3ccccc3)c3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C2(O)C(=O)N(Cc3ccccc3)c3ccccc32)cc(C)c1O
Yield: 107.6 %

Procedure:
Dissolve 1-benzyl-3-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-3-hydroxy-1,3-dihydro-indol-2-one (152 mg, 0.3 mmol) in THF (5 mL) and treat with 1.0M in THF tetrabutylammonium fluoride (0.36 mL, 0.36 mmol) for 6 h. Pour into ethyl acetate (25 mL) and wash with water (3×25 mL) and brine (25 mL). Dry (MgSO4), filter and concentrate in vacuo to give a summy residue. Purify by flash chromatography (gradient of 5% EtOAc/hexanes to 50% EtOAc/hexanes) to give 116 mg (98%) of the title compound as a white solid. MS (ES): m/z=376 (M+1−H2O); 1H NMR(DMSO-d6); δ8.26 (s, 1H), 7.54 (dd, J=1.7, 1.4 Hz, J=7.7, 7.4 Hz, 1H), 7.38-7.15 (m, 5H), 7.05 (t, J=7.4 Hz, 1H), 6.85 (m, 3H), 6.65 (s, 1H), 4.96 (q, 2H), 2.12 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15](I)=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH:30]1([C:36]#[CH:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([C:37]#[C:36][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2]
Reactant: C#CC1CCCCC1
Reactant: CCOC(=O)c1cc(Cl)nc2c1c(I)nn2C1CCCCO1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(Cl)nc2c1c(C#CC1CCCCC1)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
A solution of 6-chloro-3-iodo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (1.0 g, 2.30 mmol) and triethylamine (1.92 mL, 13.77 mmol) in THF (7.65 mL) was degassed using argon during 3 min. Cyclohexylacetylene (0.45 mL, 3.44 mmol), copper(I) iodide (0.08 g, 0.46 mmol) and tetrakis(triphenylphosphine)palladium (0.13 g, 0.11 mmol) were then added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue purified on a silica gel column chromatography using a gradient of ethyl acetate (0-5%) in cyclohexane to afford the title compound as a beige solid (0.93 g, 97%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([O:25][CH3:26])[CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:31]5[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=5)=[CH:3][C:4]=4[O:25][CH3:26])[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: COc1cc(Br)ccc1-n1c(C[C@@H]2CCN(C(=O)C3CC3)C2)n[nH]c1=O
Reactant: OB(O)c1ccc(F)cc1
Product: COc1cc(-c2ccc(F)cc2)ccc1-n1c(C[C@@H]2CCN(C(=O)C3CC3)C2)n[nH]c1=O
Yield: 72 %

Procedure:
Following the procedure described in Example 76c using 4-[4-bromo-2-(methyloxy)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one and (4-fluorophenyl)boronic acid gave the title compound as a solid (60 mg, 0.137 mmol, 72% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.27-9.05 (m, 1H), 7.58 (dd, J=5.3, 7.3 Hz, 2H), 7.34 (ddd, J=2.3, 4.0, 7.8 Hz, 1H), 7.28-7.11 (m, 3H), 4.02-3.87 (m, 3H), 3.80-3.67 (m, 1H), 3.62 (ddd, J=4.2, 8.0, 11.9 Hz, 1H), 3.49-2.96 (m, 1H), 2.77-2.36 (m, 2H), 2.32-1.99 (m, 1 H), 1.88-1.67 (m, 1H), 1.59-1.50 (m, 1H), 1.09-0.92 (m, 2H), 0.84-0.67 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:7][N:8](C)[C:9](=O)OC(C)(C)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:17].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:17].[CH:1]1([CH2:7][NH:8][CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(CC1CCCCC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCC1CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of tert-butyl N-(cyclohexylmethyl)-N-methylcarbamate (370 mg, 1.6 mmol) in 4.0 mL of ethyl acetate was added 4 M HCl-ethyl acetate (4 mL). After being stirred at room temperature for 1.5 h, the reaction mixture was concentrated in vacuo, and the residue was rinsed with hexane to obtain the title compound (266 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:11])[CH:3]=1.[N:12]([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:11][C:4]1[CH:3]=[C:2]2[C:9]([CH:10]=[N:12][NH:1]2)=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: O=N[O-]
Reactant: Cc1cc(C#N)c(C)cc1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2[nH]ncc2cc1C#N
Reaction time: 48 h
Yield: 20.9 %

Procedure:
A solution of 4-amino-2,5-dimethylbenzonitrile (preparation 31) (111 mg, 0.76 mmol) in acetic acid (5 ml) was treated with a solution of sodium nitrite (53 mg, 0.76 mmol) in water (1 ml). The resultant mixture was stirred at room temperature for 10 mins then left to stand for 48 hrs. The solvent was removed by evaporation and the residue purified by chromatography (SiO2, eluting with 50:50 hexane:ethyl acetate) to give the desired product (25 mg, 21%). 1H NMR (CD3OD) δ 2.60 (s, 3H), 7.50 (s, 1H), 8.15 (s, 1H), 8.20 (s, 1H). LRMS m/z=158.1 (M+1)+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]OS([O-])(=O)=O.[Na+]>O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCCC

Procedure:
10 ml of water and 30 mg of SDS were homogenized to an emulsion. To this emulsion, 125 ml of the ferrofluid from Example 7 (Preparation of water-based ferrofluid) was added and mixed with the dispersion from step 1 in a reactor.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:20]3([C:17]4[N:13]5[CH2:14][CH2:15][S:16][C:10]([CH2:9][OH:8])([CH3:36])[CH2:11][C:12]5=[N:19][N:18]=4)[CH2:22][CH2:21]3)=[CH:24][CH:25]=2)=[N:30][CH:31]=1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccc(Cl)cn5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(Cl)cn5)cc4)CC3)n2CCS1
Yield: 109.5 %

Procedure:
A solution of the compound (367 mg, 0.68 mmol) obtained in Example 53-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (318 mg, quant.) as a colorless solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH2:32]([O:34][C:35]1[CH:36]=[C:37]([OH:82])[C:38]([F:81])=[C:39]([N:41]([CH2:50][C:51]2[N:52]([C:62]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH:53]=[C:54]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[N:55]=2)[C:42]2[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=2)[CH:40]=1)[CH3:33].O[CH:84]1[CH2:89][CH2:88][N:87]([CH3:90])[CH2:86][CH2:85]1>C1COCC1>[CH2:32]([O:34][C:35]1[CH:36]=[C:37]([O:82][CH:84]2[CH2:89][CH2:88][N:87]([CH3:90])[CH2:86][CH2:85]2)[C:38]([F:81])=[C:39]([N:41]([CH2:50][C:51]2[N:52]([C:62]([C:75]3[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=3)([C:69]3[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH:53]=[C:54]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[N:55]=2)[C:42]2[CH:43]=[CH:44][C:45]([C:46]#[N:47])=[CH:48][CH:49]=2)[CH:40]=1)[CH3:33]
Reactant: CCOc1cc(O)c(F)c(N(Cc2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(C#N)cc2)c1
Reactant: CN1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1cc(OC2CCN(C)CC2)c(F)c(N(Cc2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(C#N)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
To triphenylphosphine (117 mg, 0.447 mmol) in THF (2 mL) at 0° C., was added diethylazodicarboxylate (71 μL, 0.447 mmol). The mixture was stirred at 0° C. for 30 min, then a solution of Intermediate 113.3 (100 mg, 0.149 mmol) and 4-hydroxy-1-methylpiperidine (34 mg, 0.298 mmol) in 1 mL THF. The mixture was allowed to warm to rt and stir 15 h, then was concentrated. The crude mixture was purified by flash chromatography (0 to 10% MeOH/CH2Cl2, gradient) to afford 77 mg of Intermediate 113.4.
Reaction SMILES: C[Mg]Br.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([C:23]3[N:28]=[CH:27][C:26]([C:29]4[O:33][N:32]=[C:31](C(OCC)=O)[CH:30]=4)=[CH:25][CH:24]=3)([CH3:22])[CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)[CH:9]=[N:10][CH:11]=1>C1(C)C=CC=CC=1.C1COCC1.C1COCC1>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([C:23]3[N:28]=[CH:27][C:26]([C:29]4[O:33][N:32]=[C:31]([C:6]([OH:5])([CH3:7])[CH3:11])[CH:30]=4)=[CH:25][CH:24]=3)([CH3:22])[CH:19]([CH3:20])[CH3:21])=[CH:14][CH:13]=2)[CH:9]=[N:10][CH:11]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C(C)(c3ccc(-c4cncc(OC)c4)cc3)C(C)C)nc2)on1
Agent: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cncc(-c2ccc(C(C)(c3ccc(-c4cc(C(C)(C)O)no4)cn3)C(C)C)cc2)c1
Reaction time: 3 h

Procedure:
Methyl magnesium bromide (300 μL of a 1.4M solution in toluene:THF (75:25), 0.420 mmol) was added to a stirred solution of 3b (40.0 mg, 0.0850 mmol) in THF (2.00 mL) at 0° C. After approximately 3 h, the reaction was quenched with saturated aqueous ammonium chloride and extracted three times with EtOAc. The combined organic extracts were washed with water and brine, dried (magnesium sulfate) and concentrated in vacuo. The crude residue was purified by preparative thin-layer chromatography on silica gel (60% EtOAc/hexanes as eluent) to afford the title compound 3c. m/z (ES) 458 (MH)+. 1HNMR (500 MHz, CDCl3): δ 9.02 (m, 1H), 8.46 (m, 1H), 8.29 (m, 1H), 7.96 (m, 1H), 7.51 (m, 4H), 7.38 (m, 2H), 6.62 (s, 1H), 3.92 (s, 3H), 3.18 (m, 1H), 1.78 (s, 3H), 1.69 (s, 6H), 0.91 (d, 3H, J=6.6 Hz), 0.88 (d, 3H, J=6.9 Hz).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:20][C@@H:21]([C:26]([NH:28][C@H:29]([C:34]([NH2:36])=[O:35])[CH2:30][CH2:31][S:32][CH3:33])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24]>>[NH:1]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:2][C:3]([NH:20][C@@H:21]([C:26]([NH:28][C@H:29]([C:34]([NH2:36])=[O:35])[CH2:30][CH2:31][S:32][CH3:33])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:5]
Reactant: CSCC[C@H](NC(=O)[C@H](N)CC(C)C)C(N)=O
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Product: CSCC[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)CNC(=O)OC(C)(C)C)C(N)=O
Yield: 95 %

Procedure:
Condensation of BocDLeuOH (2.49 g.) and HMetNH2 (1.85 g.) by the mixed anhydride method using isobutyl chloroformate gave BocDLeu-MetNH2 in 47% yield. De-t-butoxycarbonylation of BocDLeu-MetNH2 (1.70 g.) using hydrogen chloride in acetic acid gave HDLeu-MetNH2 in 78% yield. Condensation of BocGlyOSu (1.8 g.) and HDLeu-MetNH2 (1.0 g.) by the activated ester method gave BocGly-DLeu-MetNH2 in 95% yield. De-t-butoxycarbonylation of BocGly-DLeu-MetNH2 (1.35 g.) using hydrogen chloride in acetic acid gave HGly-DLeu-MetNH2 in 55% yield.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:21]2[C:16]([CH:17]=[N:18][C:19]([S:22][CH3:23])=[N:20]2)=[CH:15][CH:14]=1)[S:3]([CH3:6])(=[O:5])=[O:4].CO.[Br:26]N1C(=O)CCC1=O>>[Br:26][C:15]1[CH:14]=[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:2]([CH3:1])[S:3]([CH3:6])(=[O:4])=[O:5])[N:21]2[C:16]=1[CH:17]=[N:18][C:19]([S:22][CH3:23])=[N:20]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Solvent: CO
Product: CSc1ncc2c(Br)cc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 1-Neck round-bottom flask, N-Methyl-N-[2-(2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide (0.710 g, 2.04 mmol) Tetrahydrofuran (20.0 mL, 246 mmol), and Methanol (10 mL, 200 mmol) were added under an atmosphere of Nitrogen at room temperature . Recrystallized N-Bromosuccinimide (0.381 g, 2.14 mmol) was added portion wise over 10 minutes. The reaction was stirred at room temperature for 2 hours. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 5% methanol). The collected fractions afforded N-[2-(5-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide a yellow solid (0.72 g, 82%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[CH3:38][N:39](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[NH2:30][C:26]1([C:23]2[CH:22]=[CH:21][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:38]#[N:39])=[CH:25][CH:24]=2)[CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1nc2n(c1-c1ccc(C3(N)CCC3)cc1)-c1cccnc1Nc1ccccc1-2
Temperature: 160 °C
Yield: 8 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.09 mmol), Pd(PPh3)4(20 mg, 0.02 mmol), and zinc cyanide (33 mg, 0.27 mmol) in DMF (0.9 mL) was heated at 160° C. for 2 hour. After cooling to room temperature, the mixture was purified by HPLC to give the titled compound as a white solid (4 mg, 8%). 1HNMR (CD3OD) 400 MHz δ: 8.45 (s, 1H), 8.18 (dd, J=4.9, 1.4 Hz, 1H), 7.92 (dd, J=7.4, 1.1 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H), 7.47 (d, J=8.6 Hz, 2H), 7.43 (t, J=7.4 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.16 (t, J=8.0 Hz, 1H), 7.08 (dd, J=8.0, 1.7 Hz, 1H), 6.78 (dd, J=8.0, 4.6 Hz, 1H), 2.83-2.75 (m, 2H), 2.63-2.56 (m, 2H), 2.30-2.20 (m, 1H), 2.04-1.94 (m, 1H); LCMS: 405 [M+H].