Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:6]([C:15]([OH:17])=O)[CH2:5][O:4][CH2:3]1.[CH3:18][NH:19][CH3:20].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>C1COCC1>[CH3:18][N:19]([CH3:20])[C:15]([C@@H:6]1[CH2:5][O:4][CH2:3][C:2](=[O:1])[N:7]1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17]
Reactant: CNC
Reactant: O=C(O)[C@@H]1COCC(=O)N1Cc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@@H]1COCC(=O)N1Cc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of (3S)-5-oxo-4-(phenylmethyl)-3-morpholinecarboxylic acid (1.5 g, 6.4 mmol) (J. Chem. Soc., Perkin Trans. 1, 1985, 2577-2580) in THF (50 mL) was added dimethylamine (3.8 mL, 7.6 mmol, 2M in THF), EDC (1.46 g, 7.7 mmol), HOAt (1.06 g, 7.7 mmol) and NMM (3.5 mL, 30 mmol). The reaction mixture was stirred overnight and the THF was evaporated, replacing it with EtOAc. 1 M HCl was added and the phases were separated. The aqueous layer was extracted twice with EtOAc and the combined organics were dried over sodium sulfate. Concentration in vacuo yielded (3S)—N,N-dimethyl-5-oxo-4-(phenylmethyl)-3 morpholinecarboxamide, which was purified by RP-HPLC. LCMS: (M+H)+: 263.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:18])=[C:13]([C:15](=O)[CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:18][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:15]([CH3:16])[C:13]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1oc2ccc(OCc3ccccc3)cc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution (200 mL) of 1-[5-(benzyloxy)-2-hydroxyphenyl]ethanone (15.3 g) synthesized in Example A82(1) in N,N-dimethylformamide were added potassium carbonate (13.1 g) and ethyl bromoacetate (7.7 mL) at room temperature, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, the obtained residue was dissolved in N,N-dimethylformamide (100 mL) again, and 1,8-diazabicyclo[5.4.0]undec-7-ene (12.2 mL) was added to the solution. The reaction mixture was stirred at 80° C. overnight. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure and the obtained solid was washed with ethanol-isopropyl ether to give the title object compound (3.3 g, 17%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH2:6][OH:7])=[C:4]([F:11])[CH:3]=1.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH:6]=[O:7])=[C:8]([F:10])[CH:9]=1
Reactant: OCc1c(F)cc(Br)cc1F
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
To a solution of 4-bromo-2,6-difluorobenzylalcohol (0.200 g, 0.9 mmol) in DCM (4 ml) and DMSO (0.440 ml) was added triethylamine (1 ml, 0.72 mmol) and sulfur trioxide pyridine complex (0.570 g, 3.6 mmol) and the resulting solution was stirred at room temperature for 3 hours. The solution was diluted with Et2O and washed with 0.5M aqueous HCl, 1M sodium bicarbonate solution and brine. The organic phase was dried over MgSO4 and the solvent removed in vacuo to afford 4-bromo-2,6-difluorobenzaldehyde (0.166 g, 0.75 mmol, 84%) as a white solid. 1H NMR (CDCl3) δ 7.22 (2H, d), 10.29 (1H, br. s).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:33](=[O:34])[C@H:32]([S:35][CH2:36][C:37]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)=[O:38])[C@H:31]2[C:46]2[CH:60]=[CH:59][C:49]([O:50][CH2:51][C:52]([NH:54][CH2:55][C:56](O)=[O:57])=[O:53])=[CH:48][CH:47]=2)=[CH:26][CH:25]=1.CN1CCOCC1.[NH2:68][C@@H:69]([C:74]([OH:76])=[O:75])[C:70]([CH3:73])([CH3:72])[CH3:71].[BH4-].[Na+]>C(Cl)Cl.CO>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[C:33](=[O:34])[C@H:32]([S:35][CH2:36][CH:37]([C:39]3[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=3)[OH:38])[C@H:31]2[C:46]2[CH:47]=[CH:48][C:49]([O:50][CH2:51][C:52]([NH:54][CH2:55][C:56]([NH:68][C@@H:69]([C:74]([OH:76])=[O:75])[C:70]([CH3:73])([CH3:72])[CH3:71])=[O:57])=[O:53])=[CH:59][CH:60]=2)=[CH:28][CH:29]=1
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(Cl)cc3)C(=O)N2c2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)[C@@H](N)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [BH4-]
Solvent: ClCCl
Solvent: CO
Solvent: CN1CCOCC1
Product: CC(C)(C)[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(Cl)cc3)C(=O)N2c2ccc(Cl)cc2)cc1)C(=O)O
Reaction time: 0.5 h

Procedure:
TBTU (0.020 g, 0.063 mmol) was added to a solution of N-{[4-((2R,3R)-1-(4-chlorophenyl)-3-{[2-(4-chlorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.030 g, 0.052 mmol) and N-methylmorpholine (0.016 g, 0.157 mmol) in CH2Cl2 (5 ml) at 30° C. After 30 minutes, D-tert-leucine (0.008 g, 0.063 mmol) was added and the mixture was stirred for 30 minutes. The reaction mixture was concentrated. Toluene (2 ml) was added and evaporated. MeOH (3 ml) and sodium borohydride (0.020 g, 0.523 mmol) were added. Full conversion to the corresponding alcohol was obtained after 5 minutes. The reaction was quenched by the addition of 0.1M NH4OAc (1 ml) buffer and the mixture was concentrated. The residue was purified by preparative HPLC using an eluent of 0-50% CH3CN in 0.1M NH4OAc buffer. Freeze-drying of the pure fractions afforded the title compound (0.021 g, 58%) as a colourless solid. 1H NMR [(CD3)2SO), 400 MHz] δ0.85 (s, 9H), 2.82-2.98 (m, 2H), 3.75-3.81 (m, 2H), 3.91-3.96 (m, 1H), 4.29-4.37 (m, 1H), 4.52 (s, 2H), 4.70-4.78 (m, 1H), 5.01-5.06 (m, 1H), 6.97-6.99 (m, 2H), 7.19-7.21 (m, 2H), 7.32-7.36 (m, 8H), 7.52-7.63 (m, 1H), 8.27-8.32 (m, 1H).
Reaction SMILES: C([Li])CCC.[CH2:6]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:19](OCC)(=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(O)(=O)C>COC(C)(C)C.C1(C)C=CC=CC=1.O>[CH2:23]([O:22][C:20](=[O:21])[C:19]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:25])[CH3:24]
Reactant: c1ccc(CN2CCCCC2)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Solvent: COC(C)(C)C
Product: CCOC(=O)C(=O)c1ccccc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of n-butyllithium in toluene (20%; 65.6 g; 0.20 mol) is added over the course of from 10 to 15 min to a solution of 31 g of N-benzylpiperidine (0.175 mol) in 60 ml of tert-butyl methyl ether. The reaction mixture is heated at from 55° to 60° C. for approximately 18 h and then metered at RT into a cold (-20° C.) solution of 50.1 g of diethyl oxalate (0.42 mol) in 160 ml of toluene. The mixture is heated to RT and stirred at from 20° to 25° C. for 30 min. Acetic acid (100%; 12.6 g; 0.21 mol) and a mixture of 50 g of crushed ice and 100 g of water are then added to the reaction mixture. The phases are separated and the organic phase is washed with 50 ml of water and concentrated by evaporation in vacuo: 43.2 g (content 89%; yield 80%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:22])[NH:17][CH2:18][CH2:19][CH2:20][OH:21])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.O>[C:11]([O:15][C:16]([NH:17][CH2:18][CH2:19][CH:20]=[O:21])=[O:22])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCC=O
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 129.5 %

Procedure:
A solution of oxalyl dichloride (597 μl) in dry dichloromethane (7 ml) was cooled to −70° C. in nitrogen atmosphere, and a solution of dimethylsulfoxide (1.15 ml) in dry dichloromethane (1.5 ml) was added slowly and stirred for 30 minutes at −70° C. To the reaction mixture was added a solution of (3-hydroxypropyl)carbamic acid tert-butyl ester (1.0 g) in dry dichloromethane (7 ml) slowly to maintain the reaction temperature at −60° C. and stirred for 30 minutes at −70° C. To the reaction mixture was added triethylamine (3.98 ml) slowly to maintain the reaction temperature at −60° C. Then the reaction mixture was allowed to warm to room temperature. To the reaction mixture was added water (10 ml) and stirred for 10 minutes, then the organic layer was separated. The aqueous layer was extracted with dichloromethane (50 ml×2). The organic layer was combined and washed with brine, dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 3-tert-butoxycarbonylaminopropionaldehyde (1.28 g), that was used crude in the next reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[N:14]=[N:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:17]=1[NH:27][C:28](=[O:30])[CH3:29].C([O-])(=O)C.[Na+].[CH:36]([NH2:38])=O.C(OC(=O)CC)(=O)CC>[Cu]I.C(OCCCC)(=O)C>[C:36]([C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[N:14]=[N:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:17]=1[NH:27][C:28](=[O:30])[CH3:29])#[N:38]
Reactant: NC=O
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Agent: [Cu]I
Agent: CC(=O)[O-]
Agent: CCC(=O)OC(=O)CC
Solvent: CCCCOC(C)=O
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
2-Bromo-4,6-dinitro-2'-acetylamino-4'-(N,N-diethylamino)azobenzene (2.4 parts), copper (I) iodide (0.95 parts), anhydrous sodium acetate (1.2 parts), formamide (1.8 parts), propionic anhydride (2.6 parts) and n-butyl acetate (44 parts) are mixed together are heated, with stirring, to 110° C. during 15 minutes. The temperature is maintained for 30 minutes when reaction is adjudged complete by thin layer chromatography. The mixture is cooled to room temperature and poured into petroleum ether (boiling range 60-80° C.) (400 parts). The precipitate is collected, washed with petroleum ether (100 parts) and dried. 2-cyano-4,6-dinitro-2'-acetylamino-4'-(N,N-diethylamino)azobenzene is obtained in 83.5% yield.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:16][CH3:17])[C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:9]2)=[CH:4][CH:3]=1.[CH3:18][N:19](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[C:18]([C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:16][CH3:17])[C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:9]2)=[CH:4][CH:3]=1)#[N:19]
Reactant: CN(C)C=O
Reactant: COc1cc2ccc(Br)cc2cc1NC(C)=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: COc1cc2ccc(C#N)cc2cc1NC(C)=O
Temperature: 120 °C

Procedure:
To a solution of N-(7-bromo-3-methoxy-naphthalen-2-yl)-acetamide (1.2 g, 4.0 mmol) in a previously degassed mixture of water and N,N-dimethylformamide (3/1, 40 mL) was added zinc cyanide (0.28 g, 2.4 mmol) followed by tris(dibenzylideneacetone)dipalladium(0) (0.18 g, 0.22 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (0.27 g, 0.48 mmol) and the resulting mixture was heated at 120° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extracts were washed 3 times with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc) to afford 0.621 g of N-(7-cyano-3-methoxy-naphthalen-2-yl)-acetamide as a cream colored solid. MS=241 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>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>[C:10]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1)#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1ccc(Br)nc1
Reactant: C#CCCCCCCCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
A mixture of 6-bromonicotinaldehyde (500 mg, 2.69 mmol), 1-dodecyne (680 mg, 4.09 mmol), triphenylphosphine (23 mg, 0.09 mmol), triethylamine (470 ml, 3.38 mmol) and bis(triphenylphosphine)palladium(II) chloride (94 mg, 0.13 mmol) in THF (10 mL) was stirred under argon at rt for 30 min. Copper(I) iodide (21 mg, 0.11 mmol) was added and the mixture was stirred for 21 hours at rt. The solvent was removed under reduced pressure. The residue was diluted with a saturated aqueous solution of NH4Cl (20 mL) and extracted with Et2O (50 ml+2×20 mL). The combined organic layers were dried over MgSO4 and the solvent was removed under reduce pressure. The residue was purified by flash chromatography (c-Hex/EtOAc 4/1) to give the title compound as yellow oil (218 mg, 29%). 1H NMR (CDCl3, 300 MHz) δ 10.1 (s, 1H), 9.00 (s, 1H), 8.11 (d, 1H, J=8.1 Hz), 7.52 (d, 1H, J=8.1 Hz), 2.49 (t, 2H, J=7.1 Hz), 1.67 (m, 2H), 1.47 (m, 2H), 1.28 (m, 12H), 0.89 (t, 3H, J=6.8 Hz). M−(LC/MS(ESI)): 270.3; M+(LC/MS(ESI)): 272.4. HPLC (Condition A), Rt: 5.23 min (HPLC purity: 98.3%).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)#[N:14].C([O-])([O-])=O.[Na+].[Na+].[Na+].[Cl-]>C(O)C.O.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>[NH2:12][CH:7]1[C:6]2[CH:5]=[N:4][CH:3]=[C:2]([C:18]3[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[CH:16][CH:17]=3)[C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: NC1CCCc2c(Br)cncc21
Reactant: N#Cc1ccc(B(O)O)cc1
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: [Cl-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(-c2cncc3c2CCCC3N)cc1
Temperature: 85 °C
Yield: 185.8 %

Procedure:
In a 100 mL round-bottomed flask, (rac)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (intermediate A-1[D]) (681 mg, 3 mmol) and 4-cyanophenylboronic acid (540 mg, 3.6 mmol) were dissolved in ethanol (54 mL) to give a light brown solution. Na2CO3 (350 mg, 3.3 mmol), dissolved in water (8.9 mL) was added followed by tetrakis(triphenylphosphine)palladium (0) (104 mg, 90 μmol) after evacuation and replacing 5 times with Argon. The solution was then heated at 85° C. overnight. The reaction was treated with an aq. 10% NaCl solution and extracted with AcOEt (3×). The organic phases were washed again with an aq. 10% NaCl solution, dried over Na2SO4, filtered and evaporated under reduced pressure to give 1.39 g brown foam which was purified by flash chromatography (50 g SiO2, Telos-cartridge, CH2Cl2/MeOH (5 to 7.5%)) and precipitated from CH2Cl2 with n-pentane to give the title compound (605 mg, 81%) as a light brown foam. MS: 250.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:15][CH2:14]2)=[CH:6][C:5]=1Cl.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.[CH2:56]([O:58]/[CH:59]=[CH:60]/B1OC(C)(C)C(C)(C)O1)[CH3:57]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:15][CH2:14]2)=[CH:6][C:5]=1/[CH:57]=[CH:56]/[O:58][CH2:59][CH3:60]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N2CCN(c3ccccc3C)CC2)cc1Cl
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CCO/C=C/c1cc(N2CCN(c3ccccc3C)CC2)c([N+](=O)[O-])cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
In a 10 ml round bottom flask equipped with a magnetic stir bar and a nitrogen inlet, the 2-chloro-5-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid methyl ester 10a (115.70 mg, 0.30 mmol) was combined dry with the tricyclohexylphosphine (20.00 mg, 0.07 mmol) and was then taken up in clean, dry 1,4-dioxane (0.75 ml, 8.77 mmol) and the mixture was stirred at room temperature under nitrogen atmosphere until all solids were in solution. While that was stirring, the potassium phosphate tribasic (126.00 mg, 0.59 mmol) was dissolved in water (0.50 ml, 27.75 mmol) and once complete dissolution was achieved, the basic solution was added to the stirring dioxane solution. The reaction mixture was then placed under vacuum for 10 min and was then flushed with nitrogen. The 2-((E)-2-ethoxy-vinyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (64.60 mg, 0.33 mmol) was added to the solution, and the system was degassed once more. After flushing the system with nitrogen once more, the tris(dibenzylideneacetone)dipalladium (27.00 mg, 0.03 mmol) was added in one portion and the flask was fitted with a jacketed reflux condenser and the system was purged under vacuum once more. The reaction mixture system was then flushed with nitrogen and warmed to 100° C. The reaction was allowed to stir overnight under nitrogen at elevated temperatures. The reaction was cooled to room temperature and the mixture was filtered through Celite, washing heavily with ethyl acetate. The liquid filtrate was then collected and the solvent was removed under reduced pressure, absorbing the residue onto Celite. The product was then purified using silica gel column chromatography, eluting a gradient of 100% heptanes to 75% ethyl acetate in heptane. The product 2-((E)-2-ethoxy-vinyl)-5-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid methyl ester 10b (97.10 mg, 0.23 mmol), was isolated as an off-white, slightly yellowish solid. LCMS (m/e)=426 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[CH3:27][C:28]1[NH:29][CH:30]=[CH:31][N:32]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:18])=[O:19])[CH:5]([CH2:4][CH2:3][CH2:2][N:29]3[CH:30]=[CH:31][N:32]=[C:28]3[CH3:27])[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCl)CCC2c2ccc(F)cc2)cc1
Reactant: Cc1ncc[nH]1
Product: Cc1ccc(S(=O)(=O)N2C(CCCn3ccnc3C)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=442.2 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 2-methyl-1H-imidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[S:11].[C:21](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[N:12][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[S:11][CH3:21]
Reactant: O=C(NC(=S)Nc1c(Cl)cccc1Cl)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSC(=NC(=O)c1ccccc1)Nc1c(Cl)cccc1Cl
Yield: 85 %

Procedure:
19.5 g (0.06 M) of N-(2,6-dichlorophenyl)-N'-benzoyl thiourea, 5.5 g (0.04 M) of ground potassium carbonate, 5.1 ml (0.08 M) of methyliodide and 200 ml of acetone are boiled in a reflux for 4 hours under energetic shaking. The acetone is distilled off. 200 ml of water are added to the residue and it is then filtered. The sediment on the filter is washed to a neutral pH. After drying 20.2 g (99% of the theoretical yield) of N-(2,6-dichlorophenyl)-N'-benzoyl-S-methylisothiourea are obtained with melting point 127-129° C. This product being recrystallized from ethyl alcohol gives the corresponding isothiourea with a melting point of 128°-130° C. and 85% yield of the theoretical one.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:25])=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]([F:18])=[C:7]([OH:17])[C:8]=1[NH:9][C:10](=O)[C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])#[N:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:18][C:6]1[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([CH3:25])[C:3]([C:1]#[N:2])=[C:8]2[C:7]=1[O:17][C:10]([C:11]([CH3:14])([CH3:15])[CH2:12][OH:13])=[N:9]2
Reactant: Cc1c(C#N)c(NC(=O)C(C)(C)CO)c(O)c(F)c1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(C)(C)CO)nc2c1C#N
Temperature: 25 °C
Yield: 67.7 %

Procedure:
N-(3-Cyano-6-fluoro-5-hydroxy-2-methyl[1,1′-biphenyl]-4-yl)-3-hydroxy-2,2-dimethylpropanamide (I-98) (184 mg, 0.54 mmol) was dissolved in toluene (3.7 ml), pyridinium p-toluenesulfonate (34 mg, 0.13 mmol) was added, followed by stirring under heat for 15 hours. After cooling to room temperature, this was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was recrystallized and purified with diisopropyl ether/ethyl acetate to obtain the entitled compound (118.6 mg, 68%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH2:21].CS([C:25]1[N:30]=[CH:29][C:28]2=[CH:31][CH:32]=[C:33]([C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)[N:27]2[N:26]=1)=O.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:21][C:25]1[N:30]=[CH:29][C:28]2=[CH:31][CH:32]=[C:33]([C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)[N:27]2[N:26]=1
Reactant: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1N
Reactant: CS(=O)c1ncc2ccc(-c3cccnc3)n2n1
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1Nc1ncc2ccc(-c3cccnc3)n2n1
Temperature: 130 °C
Yield: 33.1 %

Procedure:
Into a 8-dram vial, 2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-phenylamine (40.0 mg, 0.137 mmol), 2-Methanesulfinyl-7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazine (80.9 mg, 0.313 mmol), Cesium fluoride (41.7 mg, 0.274 mmol), tert-Butyl alcohol (0.80 mL) and N,N-Diisopropylethylamine (0.0478 mL, 0.274 mmol) were added. The reaction mixture was heated at 130° C. overnight. HPLC suggested little if any SM. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give a [2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-(7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine yellow solid (22 mg, 33%). LCMS (E/I+) 486.18 (M+H). NMR 1H (DMSO-d6)-9.35 (s, 1H), 8.97 (s, 1H), 8.65 (d, 1H, J=8.50 Hz), 8.55 (s, 1H), 7.97 (s, 1H), 7.69 (d, 1H, J=8.50 Hz), 7.50 (t, 1H, J=5.95 Hz), 7.31 (d, 1H, J=4.25 Hz), 6.97 (d, 1H, J=4.25 Hz), 6.73 (s, 1H), 6.58 (d, 1H, J=9.35 Hz), 4.05 (d, 2H, J=11.87 Hz), 3.91 (d, 2H, J=11.87 Hz), 3.83 (s. 3H), 3.67 (t, 2H, J=11.87 Hz), 3.52 (d, 2H, J=11.87 Hz), 3.13 (d, 2H, J=11.87 Hz), 2.73 (t, 2H, J=11.87 Hz), 2.16 (d, 2H, J=11.87 Hz), 1.71 (q, 2H, J=11.87 Hz).