Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]#[N:24])=[CH:21][NH:20][N:19]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]#[N:24])=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)cc1
Reactant: N#Cc1c[nH]nc1N
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(F)cc3)nc12
Yield: 38.5 %

Procedure:
Reaction of 1-(4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (234 mg, 1.0 mmol), prepared from commercially available 4-fluoro-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (118 mg, 39%). MS (ISP) 306.9 [(M+H)+]; mp 198° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([S:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]([NH:22][C:23]([NH2:25])=[O:24])=[C:17]([N+:19]([O-])=O)[CH:18]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[H][H]>CO.COCCO.[Ni]>[F:26][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([S:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]([NH:22][C:23]([NH2:25])=[O:24])=[C:17]([CH:18]=2)[NH2:19])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: COCCO
Solvent: CO
Product: NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1N

Procedure:
61.5 g of 5-(3-trifluoromethylphenylsulfonyloxy)-2-ureidonitrobenzene in 200 ml of methanol and 200 ml of 2-methoxyethanol are hydrogenated under normal pressure with a catalytic amount of Raney nickel. After hydrogen uptake is complete, the catalyst is filtered off with suction, washed with methanol and the solution is evaporated under reduced pressure, 1 liter of water is added, and the solid is filtered off with suction, washed with water and dried over NaOH, melting point 172° C., decomposition.
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[O:11][CH:10]2[C:7]([C:33](=[O:41])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:8](=[O:32])[N:9]2[C:12](=[C:29]([CH3:31])[CH3:30])[C:13]([O:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)=[O:4].O>C(O)(=O)C.[Zn]>[C:3]([CH:5]1[O:11][CH:10]2[C:7]([C:33](=[O:41])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:8](=[O:32])[N:9]2[C:12](=[C:29]([CH3:31])[CH3:30])[C:13]([O:15][CH:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)(=[O:4])[CH3:2]
Reactant: CC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)CCl)OC12
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)C)C2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of 1.59 g of diphenylmethyl α-(3ξ-chloroacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 16 ml of acetic acid is added 1.5 g of zinc powder, and the mixture stirred at room temperature for 1 hour, then poured into water and extracted with methylene chloride. The extract is washed with water, dried on magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on 30 g of silica gel containing 10% water and eluted with benzene containing 10% ethyl acetate to yield 1.21 g of diphenylmethyl α-(3ξ-acetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 81% yield.
Reaction SMILES: NC(N)=O.S(=NC(N)=O)(=O)=O.[NH2:12][C:13]1[N:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]3[CH:26]=[C:27]([F:32])[C:28]([NH:30][CH3:31])=[CH:29][C:22]=3[O:21][CH2:20]2)=[CH:15][CH:14]=1.[CH3:33][C:34]1[S:38][C:37]([S:39]([NH:42][C:43](=O)[O:44]CC)(=[O:41])=[O:40])=[CH:36][CH:35]=1>>[F:32][C:27]1[C:28]([NH:30][CH3:31])=[CH:29][C:22]2[O:21][CH2:20][N:19]([C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:43]([NH:42][S:39]([C:37]4[S:38][C:34]([CH3:33])=[CH:35][CH:36]=4)(=[O:40])=[O:41])=[O:44])=[N:18][CH:17]=3)[C:24](=[O:25])[C:23]=2[CH:26]=1
Reactant: CCOC(=O)NS(=O)(=O)c1ccc(C)s1
Reactant: CNc1cc2c(cc1F)C(=O)N(c1ccc(N)nc1)CO2
Agent: NC(=O)N=S(=O)=O
Agent: NC(N)=O
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc(NC(=O)NS(=O)(=O)c3ccc(C)s3)nc1)CO2

Procedure:
Analogous to the sulfonylurea urea coupling method described in Ex 5, 3-(6-aminopyridin-3-yl)-6-fluoro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one was coupled with ethyl 5-methylthiophen-2-ylsulfonylcarbamate to yield 1-(5-(6-fluoro-7-(methylamino)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)pyridin-2-yl)-3-(5-methylthiophen -2-ylsulfonyl)urea. RP-HPLC: 2.7 min; ES-MS (M+H)+=492.3; 1H-NMR (MeOH-d4) δ (ppm): 2.5 (s, 3), 2.86 (s, 3), 5.5 (s, 2), 6.2 (d, 1), 6.8 (d, 1), 7.4 (d, 1), 7.46 (d, 1), 7.6 (d, 1), 7.8 (dd, 1), 8.3 (d, 1).
Reaction SMILES: [CH:1]([C:3]1[N:12]2[C:6]([CH:7]3[CH2:20][N:19]([CH3:21])[C:18](=O)[C:17](=O)[N:8]3[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH2:11]2)=[CH:5][CH:4]=1)=O.B#B>>[CH3:21][N:19]1[CH2:18][CH2:17][N:8]2[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH2:11][N:12]3[C:3]([CH3:1])=[CH:4][CH:5]=[C:6]3[CH:7]2[CH2:20]1
Reactant: CN1CC2c3ccc(C=O)n3Cc3ccccc3N2C(=O)C1=O
Agent: B#B
Product: Cc1ccc2n1Cc1ccccc1N1CCN(C)CC21

Procedure:
According to the method illustrated by Examples 1 and 2, the 12-formyl-2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine is reduced with diborane, to yield the 2,12-dimethyl-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine, which is converted into its monomaleate melting at 173°-175°.
Reaction SMILES: Br[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[N-:10]=[N+:11]=[N-:12].[Na+].O>CN(C=O)C>[N:10]([C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1)=[N+:11]=[N-:12]
Reactant: N#Cc1ncccc1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ncccc1N=[N+]=[N-]

Procedure:
A solution of 3-bromo-2-cyanopyridine (Chem. Pharm. Bull, 1985, 33, 565) (2.6 g, 14.2 mmol) and sodium azide (1.0 g, 15.3 mmol) in DMF (30 ml) was heated at 90° C. for 16 h. The resulting mixture was cooled, water was added and the whole was extracted with ethyl acetate. The combined extracts were washed with saturated brine and dried over magnesium sulphate. Evaporation of the solvent gave the product as an oil, which was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petrol (1:3 to 1:1) as eluent to afford the product. MS (EI) m/z 145; 1H NMR (d6-DMSO) 8.50 (1H, d), 8.09 (1H, d), 7.77 (1H, dd).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([O:13][CH3:14])=[N:6][CH:7]=[C:8]2[O:11][CH3:12])[N:3]=1.[CH3:15][O:16][C:17]1[C:22]([S:23](Cl)(=[O:25])=[O:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=[CH:19][N:18]=1.N1C=CC=CC=1.CS(C)=O>ClCCl.C(#N)C>[CH3:14][O:13][C:5]1[N:4]2[N:3]=[C:2]([NH:1][S:23]([C:22]3[C:17]([O:16][CH3:15])=[N:18][CH:19]=[CH:20][C:21]=3[C:27]([F:30])([F:28])[F:29])(=[O:24])=[O:25])[N:10]=[C:9]2[C:8]([O:11][CH3:12])=[CH:7][N:6]=1
Reactant: COc1nccc(C(F)(F)F)c1S(=O)(=O)Cl
Reactant: COc1cnc(OC)n2nc(N)nc12
Solvent: CC#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1nccc(C(F)(F)F)c1S(=O)(=O)Nc1nc2c(OC)cnc(OC)n2n1

Procedure:
A mixture of 0.75 g (93.8 mmol) of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine, 2.1 g (7.6 mmol) of 2-methoxy-4-(trifluoromethyl)pyridine-3-sulfonyl chloride, and 10 mL of dry acetonitrile was prepared and to this was added at ambient temperature with stirring and means to exclude moisture from the system 0.61 mL (7.6 mmol) of dry pyridine, 43 microliters (0.6 mmol) of dry dimethyl sulfoxide, and a small quantity of dry 4A molecular sieves. The mixture was stirred for 5 days. Another 1.0 g (3.4 mmol) of 2-methoxy-4-(trifluoromethyl) pyridine-3-sulfonyl chloride and 0.30 mL (3.5 mmol) of dry pyridine were added and the mixture stirred another 2 days. Another 0.30 mL (3.5 mmol) of dry pyridine was added and stirring continued for 4 more days. The mixture was then diluted with 100 mL of dichloromethane and the resulting mixture was washed with 2×100 mL of 2N aqueous hydrochloric acid, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The tan solid residue was chromatographed on silica gel eluting with a mixture of dichloromethane and ethanol to obtain 0.90 g (54 percent of theory) of the title compound as a white solid melting at 214°-216° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][OH:4].S(=O)(=O)(O)[OH:12].[Mn]([O-])(=O)(=O)=O.[K+].S([O-])(O)=O.[Na+]>CCOCC.O>[CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:3]([OH:12])=[O:4]
Reactant: CCCCCCC(C)CO
Reactant: O=S(=O)(O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCCCCCC(C)C(=O)O
Temperature: 0 °C
Yield: 71 %

Procedure:
To 21.2 g (147 mmol) of (-)-2-methyloctanol were added 330 ml of water and 46.4 g of concentrated sulfuric acid with stirring to form an emulsion. To this emulsion was added dropwise 63.4 g (401 mmol) of potassium permanganate over 7 hours. The reaction liquid was added with 51.5 g of sodium hydrogen sulfite, 70 ml of ice water and 200 ml of ether and poured into 270 ml of ice water. After the separation of two layers, the reaction product was extracted from water layer with ether and further with a 10% aqueous solution of sodium hydroxide, which was added with ice and further with concentrated sulfuric acid to adjust pH to not more than 1. The reaction product was extracted from the water layer with chloroform, washed with water, dried on magnesium sulfate and filtered off, and then the filtrate was concentrated and distilled under a reduced pressure to obtain 16.5 g (yield 71%) of a colorless and transparent liquid of (+)-2 -methyloctanoic acid.
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([CH3:36])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[C:25]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH:26]=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+]>CO>[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:19]3[O:20][C:21]([CH3:22])=[C:17]([CH2:16][CH2:15][O:14][C:11]4[CH:10]=[CH:9][C:8]([O:7][C:5]([CH3:36])([CH3:6])[C:4]([OH:37])=[O:3])=[CH:13][CH:12]=4)[N:18]=3)[CH:24]=2)=[CH:34][CH:33]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4ccc(F)cc4)c3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(-c2cccc(-c3ccc(F)cc3)c2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
2-Methyl-2-{4-[2-(5-methyl-2-[4′-fluorobiphenyl-3-yl]-oxazol-4-yl)ethoxy]phenoxy}propionic acid ethyl ester (24.7 mmol) was dissolved in methanol (200 mL) and 2N NaOH (150 mL) was added. The resulting cloudy solution became clear after 30 min and the reaction was stirred vigorously overnight. The solution was concentrated under reduced pressure, diluted with H2O (100 mL) and acidified to pH=1 with 5N HCl. The mixture was extracted with ethyl acetate (2×200 mL), dried (MgSO4), and concentrated under reduced pressure to provide an oil. The oil (8.23 g) was recrystallized from ethyl acetate (24 mL) and hexanes (56 mL) to afford 2-(4-{2-[2-(4′-fluorobiphenyl-3-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl-propionic acid (7.57 g, 67%) as colorless needles after drying at 50° C. under vacuum for 6 h: Rf=0.12 in 6:4 ethyl acetate:hexanes; 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.77-7.73 (m, 3H), 7.57 (t, J=7.6 Hz, 1H), 7.30 (t, J=9.2 Hz, 2H), 6.83 (d, J=9.2 Hz, 2H), 6.78 (d, J=9.2 Hz, 2H), 4.14 (t, J=6.4 Hz, 2H), 2.90 (t, J=6.4 Hz, 2H), 2.35 (s, 3H), 1.39 (s, 6H); MS (EI) 476.2 (M+H)+, 474.2 (M−H)−.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9](=[O:15])[N:8]([CH3:16])[C:7](=[O:17])[CH:6]=1>C(O)C>[NH:2]([C:5]1[N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9](=[O:15])[N:8]([CH3:16])[C:7](=[O:17])[CH:6]=1)[NH2:3]
Reactant: NN
Reactant: CC(C)Cn1c(Cl)cc(=O)n(C)c1=O
Solvent: CCO
Solvent: O
Product: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Temperature: 25 °C

Procedure:
Hydrazine hydrate (6.5 ml) was added to a solution of 6-Chloro-1-isobutyl-3-methylpyrmidine-2,4(1H,3H)-dione (10 g) in ethanol (40 ml). The mixture was heated at reflux for 5 hours, cooled to room temperature and then evaporated under reduced pressure. The residue was crystallized from ethanol to give the subtitle compound (6.7 g). Mass: 213.00 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH2:25])=[C:14]([C:16](=[O:24])[NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH:15]=2)=[CH:6][CH:5]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.O>[NH2:25][C:13]1[N:12]=[CH:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:26])=[O:2])=[CH:9][CH:8]=2)=[CH:15][C:14]=1[C:16](=[O:24])[NH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1

Procedure:
190 mg of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid methyl ester are dissolved in 20 ml of MeOH. 175 mg Na2CO3 in 6 ml of water are added.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]([CH3:21])[C:17]([O:19]C)=O)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([NH2:26])[CH2:23][CH2:24][NH2:25]>>[NH2:25][CH2:24][CH2:23][CH2:22][NH:26][C:17](=[O:19])[CH:16]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]([OH:11])=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[CH:8]=1)[CH3:21]
Reactant: COC(=O)C(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: NCCCN
Product: CC(C(=O)NCCCN)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
146 g of methyl 3,5-di-tert-butyl-4-hydroxyphenylpropionate and 370 g of 1,3-propanediamine are heated together at 130° C. for 11 hours, after which the mixture is evaporated down under reduced pressure. The residue melts at 75°-80° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1([S:14]([C:17]2[C:18]([CH2:34][CH3:35])=[N:19][N:20]3[C:25]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:24][C:23](Cl)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[C:8]1([S:14]([C:17]2[C:18]([CH2:34][CH3:35])=[N:19][N:20]3[C:25]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:24][C:23]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCc1nn2c(N3CCN(C)CC3)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CCc1nn2c(N3CCN(C)CC3)cc(N3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.9 %

Procedure:
0.33 ml (3 mmol) of 1-methyl-piperazine in 5 ml of DMF was added to a solution of 0.50 g (1.2 mmol) of 3-benzenesulphonyl-5-chloro-2-ethyl-7-(4-methyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidine in 15 ml of DMF and stirred at 100° for 1 hr. After cooling to RT the reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH/NH4OH 110:10:1) and crystallization from EtOH yielded 0.04 g (69%) of 3-benzenesulphonyl-2-ethyl-5,7-bis-(4-methyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. 232-235°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25]C)=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:3]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)=[O:17])=[CH:13][CH:14]=2)[CH:3]=1
Reactant: CCc1ccc(NC(=O)Nc2ccc(Cc3cc(N)ncn3)cc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)Nc2ccc(Cc3cc(N)ncn3)cc2)cc1
Reaction time: 3 h

Procedure:
The title compound is prepared as described in Example 102 but using 6-(4-aminobenzyl)-pyrimidin-4-ylamine (see Example 157), and DMF as the solvent. The reaction mixture is stirred for 3 h. The title compound is obtained as a white solid: ES-MS: 348.0 [M+H]+; single peak at tR=6.94 min (System 2).
Reaction SMILES: [OH:1]C1C=CC(CC(CC)C(OC)=O)=CC=1.CS(C1C=CC(CCO)=CC=1)(=O)=O.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.[C:47]1([P:53]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[C:60]1([P:53](=[O:1])([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCC(Cc1ccc(O)cc1)C(=O)OC
Agent: CS(=O)(=O)c1ccc(CCO)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
Methyl 2-(4-hydroxybenzyl)butanoate (0.50 g; 2.5 mmole) and 2-[4-(methylsulfonyl)phenyl]ethanol (0.52 g, 2.5 mmole) were mixed in dichloromethane (10 ml). ADDP (0.76 g, 3.0 mmole) was added followed by addition of triphenylphosphine ((0.79 g, 3.0 mmole). The reaction was interrupted after 16 hours. Triphenylphosphine oxide formed in the reaction was filtered off and the filtrate was evaporated. Chromatography of the crude material from methanol and dichloromethane, gradient eluation from 0-32% gave 0.64 g (66% yield) of the product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:11][N:12]([CH2:15][CH2:16][C:17]#[N:18])[CH2:13][CH2:14][C:3]1=2.[H][H]>N.CO.[Ni]>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:13][CH2:14][C:3]1=2
Reactant: Cn1c2c(c3ccccc31)CN(CCC#N)CC2
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cn1c2c(c3ccccc31)CN(CCCN)CC2
Yield: 100 %

Procedure:
A mixture of intermediate (15) (0.06 mol) in NH3/CH3OH (400 ml) was hydrogenated at 20° C. with Raney Nickel (3 g) as a catalyst. After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated, yielding 14.6 g of 1,3,4,5-tetrahydro-5-methyl-2H-pyrido[4,3-b]indole-2-propanamine (intermediate 16).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH2:10][CH:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([CH3:19])[C:13]([CH3:21])([CH3:20])[CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C(C)=CC=CC=1.C(Cl)(Cl)Cl>[Cl:3][C:2]1[N:1]=[C:8]([NH:10][CH:11]2[CH2:12][C:13]([CH3:21])([CH3:20])[N:14]([CH3:19])[C:15]([CH3:17])([CH3:18])[CH2:16]2)[N:7]=[C:5]([NH:10][CH:11]2[CH2:12][C:13]([CH3:20])([CH3:21])[N:14]([CH3:19])[C:15]([CH3:18])([CH3:17])[CH2:16]2)[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN1C(C)(C)CC(Nc2nc(Cl)nc(NC3CC(C)(C)N(C)C(C)(C)C3)n2)CC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.0 g of cyanuric chloride and 20.0 g of 4-amino-1,2,2,6,6-pentamethylpiperidine were dissolved in 100 ml of xylene, and the solution was stirred at room temperature for 1 hour. 50 ml of a saturated aqueous solution of potassium carbonate were then added to the resulting solution and the mixture was stirred for a further 2 hours at 60° C. At the end of this time, water and chloroform were added to the mixture, which was then allowed to stand at room temperature. The resulting crystals were filtered off and then recrystallized from benzene, to give the title compound in the form of crystals melting at 290° C.
Reaction SMILES: [CH2:1]([C@:8]12[CH2:16][C@H:12]([C:13](=[O:15])[O:14]1)[C@@H:11]([C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20]1)=[O:18])[CH2:10][CH2:9]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][OH:32]>CO>[CH2:1]([C@@:8]1([OH:14])[CH2:16][C@H:12]([C:13]([NH:31][OH:32])=[O:15])[C@@H:11]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1O[C@@]2(Cc3ccccc3)CC[C@H](C(=O)N3CCN(c4ccccc4)CC3)[C@@H]1C2
Reactant: NO
Solvent: CO
Product: O=C(NO)[C@H]1C[C@](O)(Cc2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
To a stirred solution of (1S,2S,5S)-5-benzyl-2-[(4-phenylpiperazin-1-yl)carbonyl]-6-oxabicyclo[3.2.1]-octan-7-one (8.0 mg, 0.020 mmol) in anhydrous methanol (1.0 mL, 0.025 mol) at rt was added 1.50 M of hydroxylamine in methanol (0.396 mL). The reaction mixture was stirred at rt for 3 h. The reaction was quenched with saturated aqueous NH4Cl (15 mL), extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC with 5-95% MeCN/H2O (with 0.05% TFA) to give the pure product as a colorless solid (2.3 mg, 26% in yield). MS (ESI): (M+H)+=438.1.
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:38][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:35])([F:37])[F:36])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)nc2)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cn2)CC1
Reaction time: 18 h
Yield: 89.5 %

Procedure:
Formaldehyde (37 wt. % in H2O; 0.012 mL, 0.17 mmol) was added to a solution of 2-(2-(2-(2-((6-(piperidin-4-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (13) (27 mg, 0.056 mmol) in MeOH (2 mL) under an atmosphere of nitrogen. The resulting mixture was stirred for 15 minutes at room temperature before sodium triacetoxyborohydride (47 mg, 0.22 mmol) was added in one portion and stirring was continued at room temperature for 18 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL) then dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound 14 as a white solid (25 mg, 90%); 1H NMR (400 MHz, d4-MeOH) δ 8.77 (d, J=2.4 Hz, 1H), 8.60 (s, 1H), 8.18 (dd, J=8.6, 2.6 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.26 (d, J=6.3 Hz, 1H), 7.21-7.15 (m, 3H), 3.67 (s, 2H), 3.20-3.14 (m, 2H), 3.14-3.08 (m, 2H), 3.04 (d, J=11.7 Hz, 2H), 2.71 (tt, J=11.9, 3.9 Hz, 1H), 2.35 (s, 3H), 2.21 (td, J=12.0, 2.5 Hz, 2H), 1.96 (d, J=11.0 Hz, 2H), 1.92-1.80 (m, 2H). LCMS-A: rt 4.635 min; m/z 499 [M+H]+.