Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH:7]=[CH:6][O:5][C:4](=[O:8])[CH2:3]1.Br[C:11]([Cl:14])([Cl:13])[Cl:12].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:33]C1C(C(Cl)(Cl)Cl)OC(=O)C(C)(C)C1>>[Br:33][CH:7]1[CH:6]([C:11]([Cl:14])([Cl:13])[Cl:12])[O:5][C:4](=[O:8])[CH2:3][C:2]1([CH3:9])[CH3:1]
Reactant: CC1(C)CC(Br)C(C(Cl)(Cl)Cl)OC1=O
Reactant: ClC(Cl)(Cl)Br
Reactant: CC1(C)C=COC(=O)C1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CC1(C)CC(=O)OC(C(Cl)(Cl)Cl)C1Br
Temperature: 100 °C

Procedure:
A mixture of 1.0 g (7.93 mmol) of 3,4-dihydro-4,4-dimethyl-2H-pyran-2-one and 6.29 g (31.7 mmol) of bromotrichloromethane was heated to 100° C. Heating was maintained at 100° C. for 12 hours. During this time 600 mg (2.48 mmol) of benzoyl peroxide was added in six 100 mg portions; a 100 mg portion being added approximately every 2 hours. The reaction mixture was cooled and placed on a silica gel packed chromatography column. Elution with 20:1 hexane:ethyl acetate mixture afforded 1.45 g, 56% yield, of 5-bromo-3,4,5,6-tetrahydro-3,3-dimethyl-6-trichloromethyl-2H-pyran-2-one.
Reaction SMILES: N12[CH2:8][CH2:7][N:4](CC1)CC2.[OH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[CH:20]=O)=[CH:17][C:16]([O:22][CH3:23])=[CH:15][CH:14]=2.[CH3:24]CCCCC.C(OCC)(=O)C>C(#N)C=C>[CH3:23][O:22][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]1[O:9][CH2:24][C:8]([C:7]#[N:4])=[CH:20][C:19]2=1
Reactant: C1CN2CCN1CC2
Reactant: COc1ccc2ncc(O)c(C=O)c2c1
Reactant: CCCCCC
Solvent: CCOC(C)=O
Solvent: C=CC#N
Product: COc1ccc2ncc3c(c2c1)C=C(C#N)CO3
Temperature: 25 °C
Yield: 78 %

Procedure:
1,4-Diazabicyclo[2.2.2]octane (345 mg, 3.07 mmol, 0.25 eq) is added at room temperature to a stirred suspension of 3-hydroxy-6-methoxy-quinoline-4-carbaldehyde (2.5 g, 12.3 mmol, 1.0 eq) in acrylonitrile (25 mL) and the resulting mixture is heated under reflux for 60 hours. The reaction mixture is then cooled to room temperature and extracted with ethyl acetate (3×100 mL) and a 1N sodium hydroxide aqueous solution (50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: hexane:ethyl acetate, 5:1, v/v) to afford 6-methoxy-2H-1-oxa-9-aza-phenanthrene-3-carbonitrile as a light yellow solid (2.3 g, 78% yield).
Reaction SMILES: [CH:1]1([CH:6]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:33]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:28][CH:27]=2)[C:7]([NH:9][C:10]2[C:11]([CH3:25])=[C:12]([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[CH:14][CH:15]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>C(O)C>[NH2:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([CH:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:7]([NH:9][C:10]2[C:11]([CH3:25])=[C:12]([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:27][CH:28]=1
Reactant: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(CN2C(=O)c3ccccc3C2=O)cc1)C1CCCC1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(CN)cc1)C1CCCC1
Temperature: 25 °C

Procedure:
8.5 g (14.6 mmol) of tert-butyl(+/−)-3-(3-(2-cyclopentyl-2-(4-((1,3-dioxoisoindolin-2-yl)methyl)phenyl)acetamido)-2-methylphenyl)propanoate were initially charged in 85 ml of ethanol, and 2.35 ml (48.3 mmol) of hydrazine hydrate were added. The reaction mixture was heated under reflux overnight. After cooling to room temperature, the precipitated solid was filtered off and washed with ethanol. The filtrate was concentrated, the residue was triturated with acetonitrile and the precipitated crystals were filtered off with suction and discarded. The mother liquor was concentrated and the residue was purified by flash chromatography on silica gel (mobile phase dichloromethane/methanol/aq. ammonia 100:5:1). This gave 4.51 g (68% of theory) of the target compound.
Reaction SMILES: C([C:4]#[N:5])(=O)C.[CH2:6]([N:13]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C@H:14]([CH:22]=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:34]1CC[CH2:36][CH2:35]1>[Cl-].[Zn+2].[Cl-]>[CH2:6]([N:13]([C@@H:14]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:22]([O:23][C:35](=[O:34])[CH3:36])[C:4]#[N:5])[C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)C#N
Reactant: C1CCOC1
Reactant: O=C[C@H](Cc1ccccc1)N(Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(=O)O[C@H](C#N)[C@H](Cc1ccccc1)N(Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 83 %

Procedure:
Acetyl cyanide (4.55 ml, 64.3 mmol) was added to a mixture of N-benzyl-N-benzyloxycarbonyl-L-phenylalaninal (20.0 g, 53.6 mmol), zinc chloride (8.76 g, 64.3 mmol) and tetrahydrofuran (70 ml) at 5° C. with stirring, and the whole was stirred at 25° C. for 12 hours. After the reaction was finished, tetrahydrofuran was evaporated under reduced pressure. Water was added to the residue, and the whole was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 19.6 g (yield 83%, erythro:threo=94:6) of titled (2S, 3S)-3-[N-(benzyl)-N-(benzyloxycarbonyl) amino]-2-acetyloxy-4-phenylbutyronitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:6]=2[CH:17]=1.[C:18]([Cl:21])(=[O:20])[CH3:19]>>[ClH:21].[CH3:16][N:13]1[CH2:12][CH2:11][CH:10]([C:7]2[C:6]3[CH:17]=[C:2]([NH:1][C:18](=[O:20])[CH3:19])[CH:3]=[CH:4][C:5]=3[O:9][CH:8]=2)[CH2:15][CH2:14]1
Reactant: CC(=O)Cl
Reactant: CN1CCC(c2coc3ccc(N)cc23)CC1
Product: CC(=O)Nc1ccc2occ(C3CCN(C)CC3)c2c1
Product: Cl
Yield: 68 %

Procedure:
Beginning with a mixture of 0.018 gm (0.07 mMol) 5-amino-3-(l-methylpiperidin-4-yl)benzofuran and 15 μL (0.21 mMol) acetyl chloride, 0.0147 gm of the title compound were prepared by the procedure of EXAMPLE 18.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C(OC)=O.[CH3:14][Mg]Br.C([O:19][CH2:20][CH3:21])C>C(Cl)Cl>[NH2:1][C@@H:2]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:20]([CH3:21])([OH:19])[CH3:14]
Reactant: COC(=O)[C@@H](N)c1ccc(F)cc1
Reactant: C[Mg]Br
Reactant: CCOCC
Solvent: ClCCl
Product: CC(C)(O)[C@@H](N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of (S)-methyl 2-amino-2-(4-fluorophenyl)acetate (0.500 g, 2.73 mmol) in diethyl ether (2.0 mL) was added dropwise to a 0° C. solution of methylmagnesium bromide (3.0 M in diethyl ether) (commercially available from Sigma-Aldrich, Milwaukee, Wis., 5.46 mL, 16.38 mmol). The ice bath was then removed, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0° C., diluted with EtOAc, and quenched by the addition of saturated aqueous ammonium chloride solution. The solution was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The aqueous phase was separated and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford a yellow-brown oil. The residual oil was dissolved in DCM and passed through a Silycycle SCX column washing with MeOH and then with 7 N ammonia in MeOH. The ammonia solution was concentrated to afford (S)-1-amino-1-(4-fluorophenyl)-2-methylpropan-2-ol (0.365 g, 1.992 mmol, 73% yield) as a yellow-brown oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (s, 3H), 1.00 (s, 3H), 1.99 (s, 2H), 3.69 (s, 1H), 4.38 (s, 1H), 7.07 (t, J=8.95 Hz, 2H), 7.37 (dd, J=8.41, 5.77 Hz, 2H). m/z (ESI) 184 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:11]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]3[O:24][CH2:23]3)=[C:16]([O:25][CH3:26])[CH:15]=2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:27][CH3:28])=[CH:7][CH:8]=2)[C:3]1=[O:29].[CH:30]([NH2:33])([CH3:32])[CH3:31]>>[CH3:1][N:2]1[C:11]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([OH:24])[CH2:23][NH:33][CH:30]([CH3:32])[CH3:31])=[C:16]([O:25][CH3:26])[CH:15]=2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:27][CH3:28])=[CH:7][CH:8]=2)[C:3]1=[O:29]
Reactant: COc1ccc2cc(CCc3ccc(OCC4CO4)c(OC)c3)n(C)c(=O)c2c1
Reactant: CC(C)N
Product: COc1ccc2cc(CCc3ccc(OCC(O)CNC(C)C)c(OC)c3)n(C)c(=O)c2c1
Yield: 80 %

Procedure:
2-Methyl-3-[3-methoxy-4-(2-hydroxy-3-isopropylamino-propoxy)-phenethyl]-7-methoxy-isoquinolin-1(2H)-one was prepared analogous to Example 1b from 2-methyl-3-[3-methoxy-4-(2,3-epoxypropoxy)-phenethyl]-7-methoxy-isoquinolin-1(2H)-one and isopropylamine.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:24][N:25]1[CH2:29][CH2:28][O:27][C:26]1=[O:30]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18](/[C:21](=[N:24]/[N:25]5[CH2:29][CH2:28][O:27][C:26]5=[O:30])/[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: NN1CCOC1=O
Product: C/C(=N\N1CCOC1=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1

Procedure:
The title compound was prepared in analogy to the synthesis of example 52 from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone and 3-aminooxazolidin-2-one. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.42 (s, 1H), 8.89 (m, 1H), 8.36 (d, 1H), 8.02 (m, 2H), 7.84 (m, 1H), 7.53 (m, 1H), 6.24 (s, 2H), 4.51 (t, 2H), 4.15 (t, 1H), 4.08 (t, 2H), 2.73 (s, 1H), 2.46 (s, 3H). LCMS (method B): [MH]+=389, tR=1.87 min.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][N:6]=[C:5]2[S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[CH2:18][S:17][C:16]1=[O:21].N1C[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)CCC>C(O)C>[CH:23](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:5]2[N:4]3[CH:3]=[CH:2][N:1]=[C:9]3[CH:8]=[CH:7][N:6]=2)[C:19]1=[O:20])[CH2:24][CH2:25][CH3:26]
Reactant: C1CCNCC1
Reactant: O=C1CSC(=O)N1CCCCSc1nccc2nccn12
Solvent: CCO
Solvent: CCCC=O
Product: CCCC=C1SC(=O)N(CCCCSc2nccc3nccn23)C1=O
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
1.612 g (5 mmol) of 3-[4-(imidazo[1,2-c]pyrimidin-5-ylthio)butyl]thiazolidine-2,4-dione and 20 ml of ethanol were placed in a reaction flask, followed by stirring at 60° C. for 20 minutes, to dissolve the starting materials. After this mixture was kept standing to 50° C., an ethanol solution of 0.05 ml (0.5 mmol) of piperidine was added. Next, an ethanol solution of 0.45 ml (5 mmol) of n-butyraldehyde was added, followed by refluxing for 100 minutes. After the reaction mixture was cooled, the solvent was distilled off, followed by extraction with dichloromethane and water. After the organic layer was dried with sodium sulfate, the solvent was distilled off. The residue was eluted by column chromatography (eluent, hexane/ethyl acetate=1/4) to yield 1.052 g (55.9%, white crystal) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](O)=[O:19])[CH:8]=1)=[O:5].Cl.[NH:34]1[C:38]([CH2:39][NH2:40])=[CH:37][N:36]=[N:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[NH3:6].[NH:34]1[C:38]([CH2:39][NH:40][C:18]([C:9]2[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:21]=[C:22]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=4)[C:23]([Cl:25])=[CH:24][C:2]=3[Cl:1])[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)=[O:19])=[CH:37][N:36]=[N:35]1
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ccc(F)cn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Reactant: NCc1cnn[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N
Product: O=C(NCc1cnn[nH]1)c1cc(NC(=O)c2cc(-c3ccc(F)cn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
5-(2,4-dichloro-5-(5-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 102, 100 mg, 0.212 mmol), (1H-1,2,3-triazol-5-yl)methanamine hydrochloride (43 mg, 0.32 mmol) and HATU (121 mg, 0.32 mmol) were dissolved in dimethylformamide (5 mL) under nitrogen. Triethylamine (0.12 mL, 0.85 mmol) was added dropwise and the reaction stirred at room temperature for 1 hour. The reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL), the organic layer was collected, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 95:5:0.5 dichloromethane:methanol:ammonia to afford the title compound as a white solid (48 mg, 42%).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([N:19]([CH3:21])[CH3:20])[C:15]=1[N:16]([CH3:18])[CH3:17])[CH:6](O)CS(C)(=O)=O.C[O-].[Na+].[NH:26]([CH2:33][CH2:34][C:35]#[N:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CS(C)=O>[NH:26]([CH2:33][CH:34]([CH2:6][C:5]1[CH:13]=[C:14]([N:19]([CH3:20])[CH3:21])[C:15]([N:16]([CH3:18])[CH3:17])=[C:3]([N:2]([CH3:1])[CH3:22])[CH:4]=1)[C:35]#[N:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N#CCCNc1ccccc1
Reactant: CN(C)c1cc(C(O)CS(C)(=O)=O)cc(N(C)C)c1N(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)c1cc(CC(C#N)CNc2ccccc2)cc(N(C)C)c1N(C)C

Procedure:
A mixture of 8.96 g. of 3,4,5-tris(dimethylamino)-α-[(methylsulfonyl)methyl]benzyl alcohol, 2.56 g. of sodium methylate and 6.6 g. of β-anilinopropionitrile in 70 ml. of dimethylsulfoxide was stirred at room temperature under nitrogen for 50 minutes. The mixture was poured into 500 ml. of ice water, the separated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. By purification of the residue over aluminum oxide with benzene and recrystallization from ethanol, there was obtained α-(anilinomethyl)-3,4,5-tris(dimethylamino)hydrocinnamonitrile having a melting point of 179°-181° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14]CC=C)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].O[C:19]1[CH:24]=CC(C(C)C([O-])=O)=C[CH:20]=1.C(OC1C=CC(CCC(OCC)=O)=CC=1)C=C.C(C1C=C(CCC(OCC)=O)C=CC=1O)C=C>>[CH3:1][CH:2]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[C:12]([CH2:24][CH:19]=[CH2:20])[CH:13]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: C=CCOc1ccc(CC(C)C(=O)OC)cc1
Reactant: CC(C(=O)[O-])c1ccc(O)cc1
Agent: C=CCOc1ccc(CCC(=O)OCC)cc1
Agent: C=CCc1cc(CCC(=O)OCC)ccc1O
Product: C=CCc1cc(CC(C)C(=O)OC)ccc1O

Procedure:
Methyl 2-methyl-3-(4-allyloxyphenyl)propionate m/z 235(M+H) was prepared from methyl 2-methyl-3-(4-hydroxyphenylpropionate using the method described in Example 1 for the preparation of ethyl 3-(4-allyloxyphenyl)propionate. Methyl 2-methyl-3-(3-allyl-4-hydroxyphenyl)propionate was prepared from methyl 2-methyl-3-(4-allyloxyphenyl)propionate using the method described in Example 1 for the preparation of ethyl 3-(3-allyl-4-hydroxyphenyl)propionate. The product was isolated as an orange oil; NMR(CDCl3): 1.13(3H,d), 2.40-2.73(2H,m), 2.92(1H,q), 3.37(2H,d), 3.63(3H,s), 4.91(1H,s), 5.03-5.18(2H,m), 5.89-6.10(1H,m), 6.70(1H,m) and 6.91(2H,m); m/z 235(M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]([NH:26][CH2:27][C:28]23[CH2:37][CH:32]4[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]4)[CH2:29]2)[CH2:35]3)=[O:25])[CH:18]=1)[CH2:5][CH2:6][N:7](C)[C:8](=O)OC(C)(C)C.Cl.N>CO.O1CCOCC1>[OH:1][CH2:2][CH2:3][N:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([CH:18]=1)[C:24]([NH:26][CH2:27][C:28]12[CH2:29][CH:30]3[CH2:36][CH:34]([CH2:33][CH:32]([CH2:31]3)[CH2:37]1)[CH2:35]2)=[O:25])[CH2:5][CH2:6][NH:7][CH3:8]
Reactant: Cc1ccc(CN(CCO)CCN(C)C(=O)OC(C)(C)C)cc1C(=O)NCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CO
Product: CNCCN(CCO)Cc1ccc(C)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.8 %

Procedure:
[2-[(2-Hydroxyethyl)[[4-methyl-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]methyl]amino]ethyl]methyl-carbamic acid, 1,1-dimethylethyl ester (Example 72a, 0.285 g) was dissolved in methanol (10 ml), 4 N HCl in dioxane (10 ml) was added and the mixture stirred for 14 h at room temperature. The solution was poured into 25% aqueous ammonia solution and concentrated under reduced pressure to give the free base. This was purified by chromatography over silica gel (eluting with 8:2:0.2/dichloromethane:methanol:ammonia) to afford the title compound as an oil (0.167 g).
Reaction SMILES: Br[CH2:2][C:3](=[O:17])[C@@H:4]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:5].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[OH:26].[F-].[K+]>CN(C=O)C.ClCCl.O>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[O:26][CH2:2][C:3](=[O:17])[C@@H:4]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:5]
Reactant: Oc1ccc(F)cc1F
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)CBr
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)COc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 94.2 %

Procedure:
A mixture of (S)-benzyl 4-bromo-3-oxobutan-2-ylcarbamate (prepared according to R. V. Hoffman et al., J. Org. Chem. 2001, 66, 5790-5795) (600 mg, 2.00 mmol), 2,4-difluorophenol (312 mg, 2.40 mmol) and potassium fluoride (380 mg, 6.54 mmol) in DMF (4 mL) was stirred at r.t. for 17 h. Water (15 mL) and dichloromethane (3 mL) were added and the mixture was stirred for 30 min. The mixture was added to a phase separator. The water phase was once more stirred with dichloromethane (3 mL), and added to the phase separator. The organic phases were concentrated and the residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 3/1) to give the title compound as a white solid (658 mg, 94% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH2:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:14]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23](O)=[O:24])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:23](=[O:24])[C@@H:22]3[CH2:26][CH2:27][CH2:28][N:21]3[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NCc1ccc2c(N)nccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
5.00 g of 1-Amino-6-aminomethyl-isoquinoline and 6.20 g Boc-L-proline were dissolved in 88 mL DMF. 10.6 g of TBTU was added followed by a dropwise addition of N-methylmorpholine. Stirring was continued for 1 h at ambient temperature and the solvent was removed i.vac. The residue was extracted with 5% aqueous NaHCO3 solution and with ethyl acetate. The organic layer was separated and dried (NaSO4). The solvent was removed to give 10.7 g (quant.) of N-(1-Amino-isoquinolin-6-ylmethyl)-1-tert.butoxycarbonyl-prolinamide as an oil.
Reaction SMILES: [CH2:1]([NH:3][S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2].[H-].[Na+].F[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].O>CN(C=O)C>[CH2:1]([N:3]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2]
Reactant: CCNS(C)(=O)=O
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(c1cc(F)ccc1[N+](=O)[O-])S(C)(=O)=O
Temperature: 55 °C
Reaction time: 8 h

Procedure:
N-ethyl-methanesulfonamide (Mijs et al. J.Chem.Soc.Chem.Com. 1972 p412) (5 g 40.6 mmol) was added to a suspension of sodium hydride (1.9 g, 55% in mineral oil) in anhydrous DMF (100 mL) under nitrogen. The mixture was warmed to 55° C. for one hour and 2,4-difluoronitrobenzene (4.4 mL) was added dropwise. The reaction was stirred at 60° C. overnight, poured into water (500 mL) and the product extracted into CH2Cl2 (5×100 mL). The organic extracts were washed with water, dried over MgSO4 and evaporated to give an oily product. The remaining DMF was removed by trituration with petrol. The crude product was purified by flash chromatography (ethyl acetate:petrol 1:1) to yield the desired product which was recrystallised from ethanol. Yield 3.5 g (33%). Calculated N % 10,68 C % 41,22 S % 12,23 H % 4,23; Found N % 10,68 C % 41,39 S % 12,22 H % 4,17.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[N+:12]([O-:15])([OH:14])=[O:13].[C:16]([NH-:18])#[N:17]>C(O)C>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[N+:12]([O-:15])([OH:14])=[O:13].[NH2:17][C:16]([NH2:4])=[NH:18]
Reactant: N#C[NH-]
Agent: Cc1ccc([N+](=O)[O-])cc1N
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: N=C(N)N

Procedure:
The synthesis of WBZ4, as shown in scheme 3 below, begins with treatment of 2-methyl-5-nitroaniline (1) with 65% nitric acid in ethanol followed by the addition of cyanoamide to give the corresponding 2-methyl-5-nitroaniline-guanidine nitrate (2). Once completed, nicotinate (3) was first treated with sodium hydrate and refluxed with ethyl acetate to form methyl 6-methylnicotinylacetate. The intermediate acetate was then hydrolyzed to form 3-Acetyl-6-methylpyridine (4). The product (4) was treated with methyl dimethoxyforamide to give 3-dimethylamino-1-(3-(6-methyl-pyridyl)-2-propene-1-one (5). The nitrate salt (2) is treated with (5) and sodium hydroxide in refluxing isopropanol to give N-(2-Methyl-5-nitrophenyl)-4-(3-(6-methyl-pyridyl))-2-pyrimidine-amine (6) which is subsequently hydrogenated with 10% palladium on carbon to give N-(2-Methyl-5-aminophenyl)-4-(3-6-methyl-pyridyl)-2-pyrimidine-amine (7). The WBZ4 synthesis will consist of the reaction of α-chloro-p-toluylic acid (8) with 4-methyl-piperazine in ethanol followed by treatment with concentrated HCl to give the corresponding dihydrochloride 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (9) which is subsequently treated with thionyl chloride to give the corresponding acid chloride dihydrochloride (10). Subsequent condensation with N-(2-Methyl-5-aminophenyl)-4-(3-(6-methyl)-pyridyl)-2-pyrimidine-amine (7) in pyridine affords Formula 5 (WBZ4).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=O)[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[F:13][C:14]([F:21])([F:20])[CH2:15][NH:16][C:17]([NH2:19])=[S:18].C(=O)(O)[O-].[Na+]>C(O)C>[F:13][C:14]([F:21])([F:20])[CH2:15][NH:16][C:17]1[S:18][CH:8]=[C:7]([C:6]2[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:19]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: NC(=S)NCC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(-c2csc(NCC(F)(F)F)n2)cc1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
Slurry 4-cyanophenacyl bromide (1.4 g, 6.3 mmol), 2,2,2-trifluoroethyl-thiourea (1.0 g, 6.3 mmol) and sodium bicarbonate (529 mg, 6.3 mmol) in absolute ethanol (30 mL). Stir the mixture at reflux for 1 h under a nitrogen atmosphere. Cool to room temperature and concentrate in vacuo. Partition the residue between DCM (100 mL) and water (20 mL). Dry the organic layer over Na2SO4 and concentrate in vacuo to obtain the desired intermediate (1.7 g, 95%). MS (ES+) m/z: 284 (M+H)+.