Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:14]([CH2:26][CH3:27])[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1)[CH3:13].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[CH2:26]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][NH:25][C:9](=[O:11])[C:8]#[C:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:22][CH:23]=1)[CH3:27]
Reactant: O=C(O)C#Cc1ccccc1
Reactant: CCN(CC)CCOc1ccc(CN)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc(CNC(=O)C#Cc2ccccc2)cc1

Procedure:
A solution of 0.29 g (2 mmol) of phenylpropynoic acid, 0.44 g (2 mmol) of [4-(2-diethylaminoethoxy)phenyl]methylamine, 0.7 g (2.2 mmol) of TBTU, 0.29 g (2.2 mmol) of HOBT and 0.51 mL (3 mmol) of Hünig base in 30 mL of THF and 2 mL of DMF is stirred for 14 hours at ambient temperature. The reaction mixture is evaporated down. The purification is carried out by column chromatography on silica gel (dichloromethane/methanol (80:20)). Yield: 130 mg (18.5% of theory); C22H26N2O2 (M=350.46); calc.: molecular ion peak (M+H)+: 351; found: molecular ion peak (M+H)+: 351; Rf value: 0.39 (silica gel, dichloromethane/methanol (80:20)).
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:25]>CN(C)C=O>[CH3:25][O:1][CH:2]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C(O)c2ccccc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(c1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A solution of tert-butyl 4-(hydroxy(phenyl)methyl)benzoate (1.4 g, 4.9 mmol) was dropped to the suspension of sodium hydride (237 mg, 5.9 mmol) in N,N-dimethylformamide (20 mL) and then the mixture was stirred 0.5 hour. Then iodomethane (3.0 mL) was added to the mixture and stirred at room temperature for 2 hours. The resultant mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=6:1) to give tert-butyl 4-(methoxy(phenyl)methyl)benzoate as a colorless oil (1.25 g, 86%). 1H NMR (300 MHz, CDCl3): δ 7.95 (d, J=8.1 Hz, 2H), 7.42-7.31 (m, 7H), 5.28 (s, 1H), 3.39 (s, 3H), 1.58 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](O)=[O:12])=[CH:5][CH:4]=1.C[N:17](C)C=O.O=S(Cl)Cl.N>C1(C)C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([NH2:17])=[O:12])=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Agent: N
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Temperature: 47.5 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
(E)-3-(4-(Trifluoromethyl)phenyl)-2-propenoic acid (2400 g, 11.1 mol) and DMF (N,N-dimethylformamide)(82 ml) were added to toluene (12 L). SOCl2 (52.6 mL, 721 mmol) was added dropwise at room temperature and the mixture was stirred at 45-50° C. for 1 hour. The toluene solution cooled to room temperature was added dropwise to 25% aqueous ammonia (12L) at 5-25° C. The mixture was stirred at 45-55° C. for 1 hour. After allowing to cool to room temperature and stirring, the mixture was stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration, washed with water (12 L) and dried under reduced pressure to give (E)-3-(4-(trifluoromethyl)phenyl)-2-propenamide (2293 g, 10.7 mol, yield 96%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6]/[CH:7]=[CH:8]/[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:5])[CH3:2].[Cl-].[Li+].[Li+].[CH3:18][CH:19]([N-]C(C)C)[CH3:20].[CH:25](Br)([CH3:27])[CH3:26]>C1COCC1>[CH2:13]([O:12][C:10](=[O:11])[CH:9]([CH:25]([CH3:27])[CH3:26])[CH:8]=[CH:7][CH:6]([CH:19]([CH3:20])[CH3:18])[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH3:14]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)Br
Reactant: CCOC(=O)C/C=C/CC(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C=CC(C(=O)OCC)C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 4 %

Procedure:
To a stirred solution of 5.0 g (25.0 mmol) trans-2-butene-1,4dicarboxylic acid diethyl ester in 120 ml THf was added 6.35 g (150 mmol) anhydrous lithium chloride and the resulting suspension cooled to −78° C. 25.0 ml (50.0 mmol) of a 2 M solution of LDA in THF was added dropwise and stirring continued for 45 min. 4.7 ml (50 mmol) isopropyl bromide was then added and stirring continued for 15 min at −78° C., then 4 h at 0° C., and then 48 h at room temperature. The reaction was quenched by addition of saturated ammonium chloride solution and the mixture extracted three times with ether. The combined organic phases were washed successively with saturated ammonium chloride solution, water, and saturated brine, dried over sodium sulphate, and concentrated in vacuo. Successive flash chromatography (20% EtOAc in hexane for first column; 5% EtOAc in hexane for second column; 10% EtOAc in hexane for third column) afforded 259 mg (4%) of the title compound as a yellow oil. MS m/e (%): 302 ([M+NH4]+, 100).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:26]([N:33]=[C:34]=[O:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O1CCCC1>[CH2:26]([NH:33][C:34](=[O:35])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reactant: CCCCCCCN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCNC(=O)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (500 mg, 2.09 mM) and triethylamine in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, n-heptyl isocyanate (505 mg/ml, 3.14 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:9) to give 8h as solid. Yield: 0.600 g, 75.6%.
Reaction SMILES: P([O-])(O)(O)=O.[Na+].C(=O)(O)[O-].[Na+].[C:12]([O:15][CH:16]1[CH:23]2[CH:19]([O:20][CH2:21][CH2:22]2)[O:18][CH2:17]1)(=[O:14])[CH3:13].C(Cl)Cl>O>[C:12]([O:15][C@@H:16]1[C@H:23]2[C@H:19]([O:20][CH2:21][CH2:22]2)[O:18][CH2:17]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC1COC2OCCC12
Agent: O=C([O-])O
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 41.5 °C
Reaction time: 24 h
Yield: 34.8 %

Procedure:
To the buffer solution (104.3 g of sodium dihydrogen orthophosphate dissolved in 530 mL of water & pH adjusted to 6.0-6.5 with saturated sodium bicarbonate solution (68 g in 680 mL water) solution) hexahydrofuro[2,3-b]furan-3-yl acetate (III, 115 g) and CAL-B (17.25 g) was added at 25-35° C., heated to 38-45° C. and stirred for 24 hours. CAL-B (17.25 g) was added stirred for 16 hours, again CAL-B (11.5 g) was added at 38-45° C. and stirred for 16 hours (pH should maintain 6.0-6.5). The reaction mass was cooled to 20-30° C., methylenedichloride (1150 mL) was added to the mass and stirred for 30 minutes. The reaction mass was filtered through hyflowbed then separated the organic layer and washed with 10% sodium chloride solution (575 mL). Organic layer was distilled completely under vacuum to get title compound II (yield 40.0 g).
Reaction SMILES: O[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.[C:29](=[O:32])([O-])[O-].[Cs+].[Cs+].[Na+].[Cl-]>CN(C=O)C>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[CH2:18][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([O:32][CH2:29][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:3][CH:4]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 5 h
Yield: 95 %

Procedure:
A mixture of 4,4'-dihydroxybenzophenone (12.4 g, 57.9 mmol), 2-chloromethylquinoline (23.4 g, 132 mmol) and cesium carbonate (46.0 g, 141.2 mmol) was stirred in dry DMF (170 mL). After 5 hours, saturated aqueous NaCl was added and the light brown solid formed was collected by filtration and washed with water. The solid was suspended in ether and collected by filtration, resuspended in ethanol and collected again by filtration and dried in vacuo to afford bis(4-(2-quinolylmethoxy)phenyl) ketone (27.3 g, 95%): IR (KBr) 1635, 1600, 1505, 1250 cm-1 ; 1H NMR (300 MHz, DMSO-d6)δ5.48 (s, 4H), 7.22 (d, 4H, J=9 Hz), 7.64 (m, 2H), 7.71 (d, 4H, J=9 Hz), 7.80 (m, 2H), 8.02 (m, 2H), 8.44 (d, 2H, J=8.5 Hz); MS (DCI/NH3) m/e: 497 (M+H)+.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31]([NH:33][CH3:34])=[O:32])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:7]=1[CH:40]([F:42])[F:41].[BrH:43]>C(#N)C.CCOC(C)=O.O.[Cu]Br>[Br:43][C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31]([NH:33][CH3:34])=[O:32])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:7]=1[CH:40]([F:42])[F:41]
Reactant: Br
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C(F)F)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(C(F)F)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
Sodium nitrite (0.12 g, 1.75 mmol) was added to a 0° C. solution of 6-(N-(4-amino-3-(difluoromethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.87 g, 1.59 mmol) in acetonitrile (10 ml) and aq HBr (48%) (10 mL). The reaction mixture was stirred for 30 min at 0° C. and copper (I) bromide (0.27 g, 1.91 mmol) was added. The reaction mixture was stirred at 75° C. for 2 h and diluted with EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc/hexanes) to afford the title compound (0.38 g, 39%) as a white foam. LCMS (m/z, ES+)=607, 609 (M+H+).
Reaction SMILES: [Br-].[Mg+2].[Br-].[Cl:4][C:5]1[C:6]([F:26])=[C:7]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24]C)=[C:19]([CH:22]=[O:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1>N1C=CC=CC=1.O>[Cl:4][C:5]1[C:6]([F:26])=[C:7]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([CH:22]=[O:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Agent: [Br-]
Agent: [Mg+2]
Solvent: O
Solvent: c1ccncc1
Product: O=Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1O
Temperature: 130 °C
Yield: 100.6 %

Procedure:
Solid anhydrous magnesium bromide (3.66 g, 19.9 mmol) was carefully added to a stirred solution of 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazoline-6-carbaldehyde (2.0 g, 6.04 mmol) in pyridine (30 ml) at room temperature. The resulting suspension was heated at 130° C. for 16 hours, cooled to room temperature and concentrated to dryness to give a yellow solid. This was suspended in water (100 ml), collected by filtration and washed several times with water. The resulting yellow solid was dried to a constant weight in a vacuum oven at 40° C. to give 4-[(3-chloro-2-fluorophenyl)amino]-7-hydroxyquinazoline-6-carbaldehyde, (1.93 g, 100%); Mass Spectrum: (M+H)+ 318.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:19][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=3)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1.C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(Cl)Cl>[CH:2]([C@H:3]1[CH2:19][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=3)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1)=[O:1]
Reactant: OC[C@@H]1CC[C@H]2CN(c3ncc(F)cn3)CCN2C1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=C[C@@H]1CC[C@H]2CN(c3ncc(F)cn3)CCN2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
A mixture of 3.75 g (14.1 mmol) of (7R,9aS)-7-hydroxymethyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 5), 2.48 g (21.2 mmol) of N-methylmorpholine-N-oxide, 5.0 g of 4 Å molecular sieves, 0.495 g (1.41 mmol) of tetrapropylammonium per-ruthenate, and 375 mL of methylene chloride was stirred at ambient temperature for 2 h. The reaction was quenched with saturated sodium thiosulfate and filtered through Celite. The filtrate was washed with brine, dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 95:5 chloroform:methanol gave 2.27 g (61%) of (7R,9aS)-7-formyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[N:17]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:16]=[CH:15][C:14]=2[CH3:26])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N([Cl:34])C(=O)C1>C(#N)C>[Cl:34][C:15]1[C:14]([CH3:26])=[C:13]([C:9]2[C:10]([CH3:12])=[CH:11][C:2]([CH3:1])=[C:3]([CH:8]=2)[C:4]([O:6][CH3:7])=[O:5])[N:17]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:23])[CH3:24])[N:16]=1
Reactant: COC(=O)c1cc(-c2c(C)cnn2COCC[Si](C)(C)C)c(C)cc1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COC(=O)c1cc(-c2c(C)c(Cl)nn2COCC[Si](C)(C)C)c(C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of methyl 2,4-dimethyl-5-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)benzoate (compound 250.3, 3.0 g, 8.02 mmol) in acetonitrile (20 mL) was added NCS (1.07 g, 8.02 mmol). The mixture was stirred at room temperature overnight, then partitioned between EtOAc (200 mL) and water (50 mL). The organic layer was washed with saturated sodium thiosulfate (50 mL), brine (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified with by silica gel column chromatography (hexanes:EtOAc, 20:1) to yield the title compound as a colorless oil (2.0 g, 61%). m/z (ES+) 409 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:17]([O:24][CH2:25][CH:26]([NH:30][C:31]([O:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1)=[O:32])[C:27](O)=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C=O)C>[CH2:17]([O:24][CH2:25][CH:26]([NH:30][C:31]([O:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1)=[O:32])[C:27]([NH:1][CH:2]([C:9]1[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(NC(COCc1ccccc1)C(=O)O)OCCCNc1ccccn1
Reactant: CCOC(=O)CC(N)c1cc(Cl)cc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CC(NC(=O)C(COCc1ccccc1)NC(=O)OCCCNc1ccccn1)c1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
119.44 mg of ethyl 3-amino-3-(3,5-dichlorophenyl)propionate, 0.164 g of 3-benzyloxy-2-[3-(pyridin-2-ylamino)propoxycarbonylamino]propionic acid, 10.00 ml of DMF, 0.084 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 0.097 ml of 4-methylmorpholine are reacted together with stirring firstly for 1.5 hours at 50° C. and subsequently overnight at room temperature. After removal of the DMF by distillation, the residue is taken up in ethyl acetate, washed with water, evaporated to dryness and purified by chromatography over a short silica column (eluent ethyl acetate), giving ethyl 3-{3-benzyloxy-2-[3-(pyridin-2-ylamino)propoxycarbonylamino]propanoylamino}-3-(3,5-dichlorophenyl)propionate, RT 1.552 min, FAB-MS (M+H)+ 618.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C:12]([CH3:26])([CH3:25])[CH2:13][O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])(=O)=O)=CC=1.[C-:28]#[N:29].[K+].O>CS(C)=O>[C:28]([CH2:11][C:12]([CH3:25])([CH3:26])[CH2:13][O:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1)(=[O:16])=[O:17])#[N:29]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(C)COS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(C)(C)CC#N)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of toluene-4-sulfonic acid 3-toluene-4-sulfonyloxy-2,2-dimethylpropyl ester (5.0 g, 12.1 mmol) in DMSO (15 mL) is added KCN (789 mg, 12.1 mmol). The mixture is stirred at 80° C. for 18 h then cooled to RT. The mixture is poured into water and extracted with ether. The organic layer is dried over sodium sulfate the filtrate concentrated. The crude material is purified by column chromatography to give the title compound.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([N+:18]([O-:20])=[O:19])=[C:6]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:5]=1)C=C.I([O-])(=O)(=O)=[O:30].[Na+].C([O:38][CH2:39][CH3:40])(=O)C>O1CCCC1.O>[CH2:22]([NH:21][C:6]1[C:7]([N+:18]([O-:20])=[O:19])=[C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=[C:4]([CH2:1][CH:39]([OH:38])[CH2:40][OH:30])[CH:5]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(C)=O
Reactant: C=CCc1cc(NCc2ccccc2)c([N+](=O)[O-])c(NCc2ccccc2)n1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(NCc2ccccc2)cc(CC(O)CO)nc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
6-Allyl-N2,N4-dibenzyl-3-nitro-pyridine-2,4-diamine (1.0 g, 2.7 mmol) was suspended in a mixture of 15 ml tetrahydrofuran and 30 ml water. Upon the addition of potassium osmate (148 mg, 0.4 mmol) and sodium periodate (1.17 g, 5.4 mmol), the solution was stirred vigorously at room temperature for 30 minutes. Ethyl acetate (20 ml) was added to the reaction mixture and the phases partitioned, the organic extract dried over magnesium sulphate, concentrated in vacuo and purified by column chromatography on silica, eluting with 100% EtOAc to afford 3-(4,6-Bis-benzylamino-5-nitro-pyridin-2-yl)-propane-1,2-diol (992 mg, 91%). The intermediate diol was stirred in 20 ml acetone in the presence of sodium periodate (1.17 g, 5.5 mmol). After 2 h the solution was partitioned between EtOAc and water, the organic extract dried (MgSO4) and concentrated to give the title compound as an orange oil, (962 mg, 96%).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:18]([NH:20][C@H:21]([C:32]([NH:34]N)=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].N[C@H:37]([C:40]([NH:42][C@H:43]([C:52]([NH:54][C@@H:55]([C:65]([NH:67][C@H:68]([C:73]([NH:75][C@H:76]([C:84]([N:86]1[CH2:95][CH2:94][CH2:93][C@H:87]1[C:88]([NH:90][CH2:91][CH3:92])=[O:89])=[O:85])[CH2:77][CH2:78][CH2:79][NH:80][C:81](=[NH:83])[NH2:82])=[O:74])[CH2:69][CH:70]([CH3:72])[CH3:71])=[O:66])[CH2:56][CH2:57][C:58](=[O:64])[O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:53])[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=1)=[O:41])[CH2:38][OH:39]>>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:18]([NH:20][C@H:21]([C:32]([NH:34][C@H:37]([C:40]([NH:42][C@H:43]([C:52]([NH:54][C@@H:55]([C:65]([NH:67][C@H:68]([C:73]([NH:75][C@H:76]([C:84]([N:86]1[CH2:95][CH2:94][CH2:93][C@H:87]1[C:88]([NH:90][CH2:91][CH3:92])=[O:89])=[O:85])[CH2:77][CH2:78][CH2:79][NH:80][C:81](=[NH:82])[NH2:83])=[O:74])[CH2:69][CH:70]([CH3:72])[CH3:71])=[O:66])[CH2:56][CH2:57][C:58](=[O:64])[O:59][C:60]([CH3:63])([CH3:61])[CH3:62])=[O:53])[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=1)=[O:41])[CH2:38][OH:39])=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].[CH3:2][C:3]([CH2:4][C:5]([OH:6])=[O:7])=[O:39]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CO
Reactant: NNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)CCC(=O)O
Product: CC(=O)CC(=O)O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)CCC(=O)O
Yield: 30 %

Procedure:
In analogy to Example 1 f), 500 mg of Glu-His-Trp-NH-NH2 were reacted with 920 mg (1 mmole) of H-Ser-Tyr-D-Glu(OBut)-Leu-Arg-Pro-NH-C2H5 . 2 HCl and purified chromatographically. Yield: 491.5 mg of chromatographically pure material. The content of peptide base was 79% as per UV-spectrum (yield: 30%). [-α]D22 = -31.3° (c=1, dimethyl acetamide)
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH:11]([C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]=1)([CH3:13])[CH3:12]>>[CH:11]([C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]=1[S:6]([Cl:10])(=[O:8])=[O:7])([CH3:13])[CH3:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)c1cc2ccccc2s1
Solvent: CN(C)C=O
Product: CC(C)c1sc2ccccc2c1S(=O)(=O)Cl

Procedure:
2-i-propylbenzo[b]thiophene-3-sulfonyl chloride compound was prepared by the method of Example 40B with DMF (5.2 mmoles, 0.40 ml), using sulfuryl chloride (4.2 mmoles, 0.34 ml) and 2-i-propylbenzo[b]thiophene (2.1 mmoles, 0.37 g). Flash chromatography (1% ethyl acetate/hexanes) provided 0.17 g (29%) of a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:12])[C:4]=2[N:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[N:23][N:24]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:25]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C(OCC)(=O)C>[N:28]1[CH:29]=[CH:30][CH:31]=[C:26]([N:24]2[CH:25]=[C:21]([C:2]3[CH:11]=[CH:10][C:9]4[CH2:8][CH2:7][CH2:6][C:5](=[O:12])[C:4]=4[N:3]=3)[CH:22]=[N:23]2)[CH:27]=1
Reactant: O=C1CCCc2ccc(Cl)nc21
Reactant: CC1(C)OB(c2cnn(-c3cccnc3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1CCCc2ccc(-c3cnn(-c4cccnc4)c3)nc21
Temperature: 80 °C

Procedure:
A mixture of 2-chloro-6,7-dihydro-8(5H)-quinolinone (1.14 g, 6.3 mmol, prepared as described in J. Org. Chem. 1990, 55, 4789) and 3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-pyridine (1.7 g, 6.3 mmol, WO 2012/000896), sodium carbonate (3.15 g, 29.6 mmol) in a mixture of acetonitrile (50 ml) and water (30 ml) was purged with argon for 10 min. To this solution was added Pd[P(Ph)3]4 (270 mg, 0.23 mmol) and the solution was heated at 80° C. overnight. The reaction mixture was diluted with ethyl acetate and the water phase was separated. The organic phase was washed with brine and dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was crystallized in isopropanol/petrol ether (1:1) to give two crops of the title product as a beige solid.