Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[Cl:22][CH2:23][C:24]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][C@H:10]1[CH3:14])=[O:25]
Reactant: C[C@@H]1CN(c2ccc(Cl)cc2)CCN1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(Cl)cc2)CCN1C(=O)CCl

Procedure:
Protocol S was followed using 1-(4-Chloro-phenyl)-3-(R)-methyl-piperazine, Et3N, chloroacetyl chloride and methylene chloride. Column chromatography afforded the title compound
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11].C(NC(C)C)(C)C>C(OC(C)C)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][C:5]1[N:4]=[CH:3][C:2]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])=[CH:7][N:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ncc(Br)cn1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)OC(C)C
Solvent: CC(C)NC(C)C
Product: Cc1ncc(C#C[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Isopropyl acetate (30 mL) was added to a mixture of 5-bromo-2-methylpyrimidine (3 g, 17.3 mmol), copper(I) iodide (0.066 g, 0.35 mmol) and bis(triphenylphosphine)palladium (II) dichloride (0.243 g, 0.35 mmol) in a 100 mL 3-neck flask equipped with a condenser. The resulting solution was sparged with a stream of nitrogen for 15 minutes and kept under nitrogen during further manipulations. Trimethylsilylacetylene (3.12 mL, 22.5 mmol) and diisopropylamine (4.90 mL, 34.7 mmol) were added successively to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The dark mixture was heated at 60° C. for 15 hours, then cooled to room temperature, diluted with isopropyl acetate (15 mL) and filtered through diatomaceous earth. The filtrate was washed successively with saturated aqueous NaHCO3 (2×25 mL), 10% aqueous Na2S2O3 (20 mL) and brine, then dried (MgSO4) and concentrated under vacuum. The dark residue was purified by flash chromatography on silca gel (hexanes-ethyl acetate, gradient from 100:0-70:30) to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 0.27 (s, 9H), 2.74 (s, 3H), 8.68 (s, 2H).
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:15])([F:14])[C:5]1[CH:6]=[C:7]([CH:11](O)[CH3:12])[CH:8]=[CH:9][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>CCCCCC>[F:3][C:4]([F:15])([F:14])[C:5]1[CH:6]=[C:7]([CH:11]([Br:1])[CH3:12])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(O)c1cccc(C(F)(F)F)c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(Br)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
bromine (32.5 g≡10.4 ml) was added over 15 minutes to a stirred mixture of (±)-1-(3-trifluoromethylphenyl)-ethanol [38 g, described by Overberger et al., Org. Synth. Coll. 3, 200 (1955)], triphenylphosphine (56 g) and dry dimethylformamide (200 ml) in an atmosphere of nitrogen. The temperature of the mixture was maintained at 40°-50° C. by ice-cooling. Further bromine was added dropwise to give a permanent orange colour and after stirring for 15 minutes the mixture was poured into a mixture of ice-water (1 liter) and hexane (500 ml). The mixture was filtered and the solid material was washed well with hexane. The hexane solutions were combined, washed with water (4×100 ml), dried over sodium sulphate and distilled to give (±)-1-(3-trifluoromethylphenyl)ethyl bromide, b.p. 98°-105° C./15 mmHg, as a clear mobile oil.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][S:10](Cl)(=[O:12])=[O:11]>C(Cl)Cl.O>[CH2:1]([NH:8][S:10]([CH3:9])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)NCc1ccccc1

Procedure:
18.27 g of benzylamine were dissolved in 100 ml of methylene chloride and, while cooling with ice, 6.00 ml of methanesulfonyl chloride were very slowly added dropwise. On completion of addition of the methanesulfonyl chloride, the reaction solution was diluted with 100 ml of water, and the aqueous phase was extracted again with 50 ml of methylene chloride. The combined organic phases were washed with 1 N aqueous hydrochloric acid, dried over MgSO4 and concentrated by rotary evaporation. This gave the product (14.40 g) with a molecular weight of 185.3 g/mol (C8H11NO2S).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.O[C:14]1[CH:15]=C2C(=C[CH:23]=1)NC(=O)CC2>>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2)[CH:14]=[CH2:23]
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: O=C1CCc2cc(O)ccc2N1
Product: C=CCOc1ccc2[nH]c(=O)ccc2c1

Procedure:
In this process, a starting material, i.e., a known compound 6-hydroxy-1H-quinoline-2-one or 6-hydroxy-3,4-dihydro-(1H)-quinoline-2-one of the formula (IV), and a halogenated acetylene derivative are subjected to dehydrohalogenation according to a conventional method to give a 6-(2-propenyloxy) quinoline-2-one derivative of the formula (V), and the resulting compound (V) is subjected to cyclization reaction according to a conventional method to give a compound of the formula (VII). (Steps A, B)
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]1=[O:3].C([NH2:18])CCCCC.C1CCN2C(=NCCC2)CC1>>[O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH2:18])[C:2]1=[O:3]
Reactant: O=c1ccc2ccccc2o1
Reactant: CCCCCCN
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1cc2ccccc2oc1=O
Reaction time: 240 h

Procedure:
Coumarin (0.3775 g, 2.583 mmol), 2.0 equimolar of n-hexylamine (0.5324 g, 5.261 mmol) and 0.1 equimolar of DBU (0.0418 g, 0.275 mmol) were added and mixed in bulk. The mixture was reacted in an oven and kept at 50° C. for 10 days. The resultant crude mixture was separated by preparative Thin Layer Chromatography (TLC) (eluent: ethylacetate/n-hexane=1/4 (vol./vol.)) to give corresponding coumarin monoamine (1:2) adduct (0.8287 g, 2.378 mmol, yield=92%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[Br:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:24][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:10][CH2:29][CH2:28][CH2:27][CH2:26][Br:25])=[O:9])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:5]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: BrCCCCBr
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCBr)C1c1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
A suspension comprising 9.96 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-methoxycarbonyl-pyridine-3-carboxylic acid, 5.4 ml of 1,4-dibromobutane and 2.07 g of potassium carbonate in 60 ml of dimethylformamide was heated at 50° C. under stirring for 2.5 hours. The mixture was then cooled to room temperature, poured into 400 ml of water and extracted with diethyl ether. The ethereal extracts were then dried on anhydrous sodium sulfate and evaporated to dryness to give an oil which was purified by flash chromatography on silica gel columns, employing first chloroform and then chloroform: ethyl acetate 97:3 by volume as eluent.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].C(#N)C.N(OC(C)(C)C)=O>CN(C)C=O>[C:7]([C:6]1[C:5]([CH3:9])=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:3][CH:2]=1)#[N:8]
Reactant: CCOC(=O)c1sc(N)c(C#N)c1C
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)c1scc(C#N)c1C
Temperature: 5 °C
Reaction time: 7 h
Yield: 47.8 %

Procedure:
A solution of 20.5 g (97.5 mmol) of ethyl 2-amino-3-cyano-4-methylthiophene-5-carboxylate in 600 ml of a 1:1 mixture of acetonitrile and dimethylformamide was cooled to 5° C., and 15.7 g (146 mmol) of tert-butyl nitrite were added dropwise, during which process the temperature of the reaction mixture rose and gas was evolved vigorously. The mixture was stirred for seven hours at room temperature and concentrated on a rotary evaporator under a high vacuum, the residue was purified by column chromatography (eluant dichloromethane), and 9.1 g (48%) of the desired compound were obtained as yellow oil. 1H NMR (270 MHz, DMSO-d6): δ=1.3 (t, 3H), 2.55 (s, 3H), 4.3 (q, 2H), 8.8 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.[OH-].[NH4+]>C1COCC1>[CH3:22][O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: COC(=O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid (1,5.0 g, 0.017 moles, 1.0 equivalent) and potassium carbonate (2.5 g, 0.018 moles, 1.1 equivalent) are mixed in THF (100 mL). To this heterogeneous mixture is then added dimethyl sulfate (1.6 mL, 2.1 g, 0.017 moles, 1.0 equivalent) and the contents were then stirred at 20-25° overnight. Once the reaction is complete as measured by HPLC, ammonium hydroxide (10%, 20 mL) is added and allowed to stir for 1 hr at which time the contents are extracted with ethyl acetate (3×50 mL). The combined organic phases are washed with water (50 mL) and saline (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]2[N:41]([N:43]=[CH:44][N:45]=2)[CH:42]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[N:45]1[CH:44]=[N:43][N:41]2[CH:42]=[C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)[CH:38]=[CH:39][C:40]=12
Reactant: Brc1ccc2ncnn2c1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc3ncnn3c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 63.4 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (300 mg, 0.63 mmol) and 6-bromo-[1,2,4]triazolo[1,5-a]pyridine (149 mg, 0.75 mmol) in dry 1,4-dioxane (15 mL) were added 2M aq Cs2CO3 (2 mL) and Pd(PPh3)Cl2 (40 mg, 0.056 mmol). After addition, the mixture was heated to reflux for 2 h under N2 atmosphere. The solid was filtered off and diluted with water (50 mL) and EtOAc (100 mL), the mixture was extracted with EA (3×50 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by prep TLC to afford (S)-3-((S)-1-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (188 mg, yield: 63.5%). LC-MS Method tR=1.18 min, m/z=471, 418; 1H NMR (CDCl3): δ 1.05 (s, 3H), 1.12 (s, 3H), 1.49-1.51 (m, 3H), 2.15-2.18 (m, 2H), 2.21-2.23 (m, 1H), 2.32-2.37 (m, 1H), 2.82-2.87 (m, 1H), 3.01-3.06 (m, 1H), 5.63-5.68 (m, 1H), 7.01-7.06 (m, 2H), 7.19-7.22 (m, 3H), 7.29-7.32 (m, 3H), 7.33-7.36 (m, 2H), 7.36-7.38 (m, 1H), 7.75-7.78 (m, 1H), 7.11-7.13 (m, 1H), 8.79 (s, 1H).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[CH2:34]([CH2:36][NH2:37])[OH:35]>>[OH:35][CH2:34][CH2:36][NH:37][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccc(OC)cc4)c3)csc12
Reactant: NCCO
Product: COc1ccc(C(=O)Nc2cccc(OCc3csc4c(C(=O)NCCO)cncc34)c2)cc1

Procedure:
3-[3-(4-Methoxy-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide was prepared from 3-[3-(4-methoxy-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 15 supra) and ethanolamine (Aldrich) following the procedure described in Example 16 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22](O)[CH:23]=[CH:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([O:10][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH3:18])[CH:25]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: COc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@@H](Oc2cccc(OC)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.6 %

Procedure:
To an ice cold solution of (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.15 g, 4.69 mmol) and 3-methoxyphenol (0.56 mL, 5.158 mmol) in THF (10 mL) is added triphenylphosphine (1.84 g, 7.03 mmol) followed by the dropwise addition of diisopropyl-azodicarboxylate (1.40 mL, 7.03 mmol). Warm to room temperature and stir for 18 h. Dilute the reaction with ethyl acetate and wash with 1 N HCl, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate) and purify (silica gel chromatography, eluting with dichloromethane/ethyl acetate mixtures) to give the title compound (0.57 g, 34%).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][NH:10][CH2:11][C:12]12[CH2:17][CH:16]1[CH2:15][NH:14][CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:25]1([N:28]2[C:37]3[C:32](=[CH:33][C:34]([F:39])=[C:35](F)[CH:36]=3)[C:31](=[O:40])[C:30]([C:41]([OH:43])=[O:42])=[CH:29]2)[CH2:27][CH2:26]1>C(#N)C>[C:1]([O:5][C:6]([CH2:8][CH2:9][NH:10][CH2:11][C:12]12[CH2:17][CH:16]1[CH2:15][N:14]([C:35]1[CH:36]=[C:37]3[C:32]([C:31](=[O:40])[C:30]([C:41]([OH:43])=[O:42])=[CH:29][N:28]3[CH:25]3[CH2:27][CH2:26]3)=[CH:33][C:34]=1[F:39])[CH2:13]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)CCNCC12CNCC1C2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCNCC12CC1CN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 30.6 %

Procedure:
A mixture of 1-[N-(tert-butoxycarbonyl)ethylamino-methyl]-3-azabicyclo[3.1.0]hexane (45.3 mg, 0.18 mmol) and triethylamine (50 μl, 0.36 mmol) in acetonitrile (5 ml) was treated with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (50.0 mg, 0.18 mmol) and heated to 80° for 18 hours. Filtration of the reaction mixture provided the title product as a white solid (26.8 mg, 0.055 mmol, 31% yield). 1H NMR (CDCl3): 8.67 (s, 1H), 7.90 (d, J=15 Hz, 1H), 6.89 (d, J=7 Hz, 1H), 3.87 (bs, 2H), 3.5 (m, 5H), 3.3 (bs, 2H), 1.6 (m, 1H), 1.49 (s, 9H), 1.33 (m, 2H), 1.14 (m, 5H), 0.83 (m, 1H), 0.68 (m, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]([NH2:10])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]#[N:10])=[CH:18][CH:19]=1
Reactant: Cc1ccc(OC(C(N)=O)c2ccccc2Cl)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(OC(C#N)c2ccccc2Cl)cc1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
The product of Step A (0.650 g, 2.36 mmol) was added to phosphorous oxychloride (5.95 mL, 27 eq) at 0° C. followed by slow addition of 0.73 mL (2.2 eq) of triethylamine. The reaction mixture was warmed to room temperature for 10 minutes, refluxed for 50 minutes and then cooled to room temperature. The reaction mixture was concentrated in vacuo, and partitioned between ice water and toluene. The aqueous layer was extracted 3 times with toluene, and the combined toluene extracts were washed with 0.5N NaOH and H2O. The crude product was concentrated in vacuo and purified on a silica gel flash chromatography column (140×30 mm) eluted with 2% ethyl acetate/hexane to afford 0.555 g (91%) of the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].Cl>ClCCl>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([N:17]([S:33]([CH3:32])(=[O:35])=[O:34])[S:33]([CH3:32])(=[O:35])=[O:34])=[N:15][CH:16]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Oc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(-c2cnc(N(S(C)(=O)=O)S(C)(=O)=O)c(Cc3ccccc3)n2)cc1
Temperature: 25 °C

Procedure:
Under an argon atmosphere, 5-(4-acetoxyphenyl)-2-amino-3-benzylpyrazine (c-19) (337 mg, 1.05 mmol) was dissolved in anhydrous dichloromethane (9 mL), and to this was added triethylamine (220 μL, 1.58 mmol) and stirred at room temperature. To this was added methanesulfonyl chloride (245 μL, 3.16 mmol) and stirred for 1.5 h at the same temperature. To this was added 2 M hydrochloric acid to stop the reaction and after separating the aqueous layer and organic layer, the organic layer was washed with saturated aqueous solution of sodium sulfate and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. The residue was purified by silica gel column chromatography (28 g, n-hexane/ethyl acetate=3/1→3/2) to give 5-(4-acetoxyphenyl)-3-benzyl-2-bis(methanesulfonyl)aminopyrazine (c-39) as a yellow amorphous (241 mg, 48.3%). Rf=0.32 (n-hexane/ethyl acetate=3/2). Mp. 165.5-167° C. UV (MeOH) λmax (log ε) 306 (4.29), 293 (4.25), 259 (4.21). UV (pH PB) λmax (log ε) 336.5 (4.19), 264 (4.09). 1H NMR (400 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.59 (s, 6H), 4.36 (s, 2H), 7.20-7.26 (m, 1H), 7.26-7.35 (m, 6H), 8.11-8.17 (AA′BB′, 2H), 9.14 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6) δ 20.9, 38.5, 43.1 (1C×2), 122.7 (2C), 126.6, 128.3 (2C), 128.6 (2C), 129.5 (2C), 132.1, 137.6, 139.2, 141.5, 151.4, 152.5, 155.6, 169.0. IR (KBr, cm−1) 509, 523, 706, 756, 766, 912, 974, 1015, 1163, 1200, 1321, 1368, 1418, 1435, 1528, 1603, 1755, 3032. HRMS (FAB+) m/z 476.0936 (M+H, C21H22N3O6S2 requires 476.0950).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15](=[NH:17])[NH2:16])=[N:6]1.C([N:24](CC)CC)C.O.NN>C(O)C>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15](=[NH:16])[NH:17][NH2:24])=[N:6]1
Reactant: CCN(CC)CC
Reactant: Cc1ncc2c(C(=N)N)nn(Cc3ccccc3F)c2n1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ncc2c(C(=N)NN)nn(Cc3ccccc3F)c2n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
688 mg (approx. 2.20 mmol, purity 92%) of 1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidamide were initially charged in 10 ml of ethanol and cooled to 0° C. 891 mg (8.80 mmol) of triethylamine and 138 mg (2.20 mmol) of 80% hydrazine hydrate were added, and the mixture was stirred at room temperature for 18 h. The mixture was concentrated on a rotary evaporator, taken up in ethyl acetate and washed three times with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, concentrated on a rotary evaporator and dried under high vacuum. 654 mg (purity 93%, 92% of theory) of the target compound were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2].[CH2:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:29]>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:33]2[CH2:34][CH2:35][N:30]([CH2:28][CH3:29])[CH2:31][CH2:32]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Solvent: ClCCl
Product: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(CC)CC4)ccc3OCC)nn12
Temperature: 0 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
470 mg (1.14 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 20 ml of dichloromethane and cooled to 0° C. 390 mg (3.42 mmol) of N-ethylpiperazine are added, and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic phase is washed twice with water and dried over sodium sulphate and the solvent is removed under reduced pressure. Crystallization from ether gives 370 mg (66%) of a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[C:22](O)(=[O:26])[CH2:23][CH2:24][CH3:25]>C1COCC1>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: CCCC(=O)O
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Solvent: C1CCOC1
Product: CCCC(=O)Nc1ccc(C)c(-c2ccc(C(=O)NCC3CC3)cc2)c1
Reaction time: 72 h

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (30 mg, 0.11 mmol) and butyric acid (22.0 mg, 0.25 mmol) were mixed in THF (3 ml). Carbodiimde resin (295 mg, 0.31 mmol) was added and shaking continued for 72 h. The reaction was filtered, the resin washed with THF and methanol and the combined filtrate and washings filtered through an SPE (SCX), to give, after evaporation of the solvent under vacuum, N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)butyramide. NMR; δH [2H6]—DMSO 9.85,(1H, s), 8.60,(1H, t), 7.91,(2H, d), 7.50-7.49,(2H, m), 7.40,(2H, d), 7.21,(1H, d), 3.16,(2H, t), 2.25,(2H, t), 2.15,(3H, s), 1.59,(2H, m), 1.04,(1H, m), 0.89,(3H, t), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.14 min, MH+351.