Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:24][S:25]([CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)(=[O:27])=[O:26]>>[CH:19]([N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][N:29]([CH2:28][S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=5)[CH:23]=[CH:22][C:5]=4[C:6]=3[N:7]=2)=[N:18][CH:17]=[N:16]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC1(C)OB(c2cnn(CS(C)(=O)=O)c2)OC1(C)C
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CS(C)(=O)=O)c3)ccc1-2

Procedure:
Following the procedure for 114, 8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 27 was reacted with 1-Methanesulfonylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give 430. MS(ESI+) 471.1. 1H NMR (400 MHz, DMSO) δ 8.36 (m, 2H), 8.19 (s, 1H), 8.10 (s, 1H), 7.49 (dd, J=8.3, 1.8, 1H), 7.36 (d, J=1.7, 1H), 5.84 (m, 1H), 5.75 (s, 2H), 4.40 (t, J=5.0, 2H), 3.46 (t, J=5.0, 2H), 3.06 (s, 3H), 1.56 (d, J=6.6, 6H)
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:5]=1[C:6]([NH2:8])=[NH:7].C1O[C:18]2([CH2:23][CH2:22][N:21]([C:24](=[O:33])[C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)OC1>>[ClH:1].[C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:24]([N:21]2[CH2:22][CH2:23][C:18]3([N:7]=[C:6]([NH2:8])[C:5]4[C:4](=[CH:12][CH:11]=[CH:10][C:9]=4[O:13][CH3:14])[NH:3]3)[CH2:19][CH2:20]2)=[O:33])=[CH:30][CH:29]=1)#[N:32]
Reactant: N#Cc1ccc(C(=O)N2CCC3(CC2)OCCO3)cc1
Reactant: COc1cccc(N)c1C(=N)N
Agent: Cl
Product: COc1cccc2c1C(N)=NC1(CCN(C(=O)c3ccc(C#N)cc3)CC1)N2

Procedure:
This was prepared with 2-amino-6-methoxybenzamidine dihydrochloride (Example E) and 1-(4-cyanobenzoyl)-4-piperidone ethylene ketal by the method of Example 1 to give the title compound as a yellow solid, m.p. 252°-253° C.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:8][C:7](=[O:27])[CH2:6][CH2:5]1.[C:28](OC(=O)C)(=[O:30])[CH3:29].O>N1C=CC=CC=1>[C:28]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C@@H:11]1[CH2:10][C:9]2[C@H:4]([CH2:5][CH2:6][C:7](=[O:27])[CH:8]=2)[C@@H:3]2[C@@H:12]1[C@H:13]1[C@@:17]([CH2:19][C@@H:2]2[F:1])([CH3:18])[C:16](=[O:20])[CH2:15][CH2:14]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCO)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Reaction time: 0.75 h

Procedure:
20 g of 11β-fluoro-7α-(5-hydroxypentyl)oestr-4-ene-3,17-dione in 100 ml of pyridine are allowed to react at 25° C. for 2 h with 50 ml of acetic anhydride. 5 ml of water are then added at 0° C. and the mixture is stirred for 45 min. It is extracted with diethyl ether, washed with 2N sulphuric acid until free of pyridine and neutralized successively with saturated sodium hydrogencarbonate solution and water. After drying and concentrating in vacuo, the crude product is chromatographed on silica gel using a hexane-ethyl acetate gradient. 17 g of 7α-(5-acetoxypentyl)-11β-fluorooestr-4-ene-3,17-dione of melting point 78.4° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8](COCCOC)[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][C:32]([CH3:37])([CH3:36])[C:31]3=[O:38])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[Si](Cl)(C)(C)C.[Na+].[I-].O>CC#N.CCOC(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][C:32]([CH3:36])([CH3:37])[C:31]3=[O:38])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CN1CCCC(C)(C)C1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN2CCCC(C)(C)C2=O)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the title compound of Step (D) (70 mg, 0.11 mmol) in 2.2 ml of CH3CN, Me3SiCl (73 mg, 0.67 mmol) was added and followed by NaI (100 mg, 0.67 mmol). The mixture was stirred at room temperature for 30 min. Additional Me3SiCl (98 mg, 0.90 mmol) and NaI (135 mg, 0.90 mmol) were added in four portions and the reaction was stirred for additional 1 hr and 40 min. The reaction mixture was then added to 2 ml H2O and 30 ml EtOAc. The organic layer was separated and washed with 1 ml saturated aqueous Na2S2O3, brine, dried and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 29% solvent A (10% MeOH, 90% H2O, 0.1% TFA). and 71% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (37 mg, 62%) as a white solid, m.p. >200° C., dec., Rf=0.5(silica gel, 10:1 CH2Cl2 /MeOH).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:20]([CH3:38])=[C:21]([NH:25][C:26](=[O:37])[C:27]5[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=5)[CH:22]=[CH:23][CH:24]=4)[C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.[Br:47]C(Cl)(Cl)C(Cl)(Cl)Br>C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:20]([CH3:38])=[C:21]([NH:25][C:26](=[O:37])[C:27]5[CH:28]=[CH:29][C:30]([C:33]([CH3:34])([CH3:35])[CH3:36])=[CH:31][CH:32]=5)[CH:22]=[CH:23][CH:24]=4)[C:13]=3[CH:12]=[C:11]2[Br:47])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2c1ccn2S(=O)(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2c1cc(Br)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of Intermediate 52 (4.26 g, 8.12 mmol) in THF (150 ml) at −78° C. was added LDA (1.5 M in THF, 16.24 ml, 24.36 mmol) slowly. The resulting mixture was stirred for 1.5 hrs at −78° C. before adding a solution of 1,2-dibromo-tetrachloroethane (3.97 g, 12.18 mmol) in THF (1 ml). Stirring was continued at −78° C. for 2 hrs, then the reaction mixture was quenched by addition of sat. aqueous NH4Cl solution and warmed up to r.t. The mixture was extracted with EtOAc and the organic layer was dried, filtered, and evaporated to dryness. Purification by flash chromatography (silica gel, cyclohexane/EtOAc gradient) yielded Intermediate 53.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:40])[F:39])=[N:36][CH:37]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:31][C:32]4[CH:37]=[N:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][CH:33]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 65 °C
Yield: 76.1 %

Procedure:
A solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (1.1 g, 3.4 mmol), prepared as described in Example 244, K2CO3 (940 mg, 6.8 mmol), and 5-chloromethyl-2-trifluoromethylpyridine (800 mg, 4.1 mmol) in DMF (8.3 mL) was heated at 65° C. for 40 min. After this time, the solution was cooled to RT The reaction mixture was partitioned between water and EtOAc. The organic layer separated, washed with water and saturated aqueous NaCl. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with hexanes/EtOAc to give the title compound, 7-(4-chlorophenyl)-8-(pyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (1.25 g, 76%) as a yellow solid. HPLC: 2.84 min; MS, M+H=483; 1H NMR (CDCl3) δ 8.80 (d, J=1.4 Hz, 1H), 8.65 (Abq, J=1.6, 4.4 Hz, 2H), 8.23 (s, 1H), 7.96 (m, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.34 (m, 2H), 7.23 (m, 2H), 7.10 (m, 2H), 5.31 (2H).
Reaction SMILES: [CH:1]([C:4]1[C:9]([OH:10])=[C:8]([N+:11]([O-])=O)[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[NH2:11][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:9]=1[OH:10]
Reactant: CC(C)c1cccc([N+](=O)[O-])c1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)c1cccc(N)c1O
Temperature: 25 °C
Yield: 71.6 %

Procedure:
A solution of 6-isopropyl-2-nitrophenol (3.000 g, 16.56 mmol) and sodium hydrosulfite (11.53 g, 66.23 mmol) in ethanol (180 mL) and water (90 mL) was stirred at 80° C. for 20 h and then cooled to room temperature. The resulting orange solution was concentrated and then partitioned between dichloromethane (50 mL) and water (50 mL). The organic phase was separated and washed with brine (25 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to afford 2-amino-6-isopropylphenol as an orange solid (1.792 g, 72%). RP-HPLC Rt 8.171 min, 92% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 150 (M−H)−.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.S(Cl)(Cl)=O.[CH2:18]([C@@H:25]1[CH2:30][C@@H:29]([N:31]([CH2:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]=[CH:41][CH:40]=2)[C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH2:28][CH2:27][NH:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N>C(Cl)Cl.CO>[CH2:18]([C@@H:25]1[CH2:30][C@@H:29]([N:31]([CH2:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]=[CH:41][CH:40]=2)[C:32](=[O:37])[C:33]([F:35])([F:36])[F:34])[CH2:28][CH2:27][N:26]1[C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:13])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: N
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccc2ccccc2n1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
97 mg (0.56 mmol) of quinoline-2-carboxylic acid are reacted in analogy to Example 2j first with 58 μl (0.795 mmol) of thionyl chloride and subsequently with 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine to give the product. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.45, FD-MS: M+ =582.
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][CH:5]=1.C(N(CC)C(C)C)(C)C.[CH3:21][C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:21][C:22]([CH3:26])([CH3:25])[C:23]#[C:24][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:11])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)C#Cc1ccc(C(=O)O)cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
6-Chloronicotinic acid methyl ester (500 mg; 2.93 mmol) was suspended in 1,4-dioxane (3 ml) in a 5 ml reaction vial. To the vessel was added dichlorobis(triphenylphosphine)palladium(II) (70 mg; 3 mol %), copper iodide (12 mg), N,N-diisopropylethylamine (0.63 ml; 3.5 mmol) and 3,3-dimethylbut-1-yne (0.44 ml; 3.5 mmol). The vessel was sealed and the mixture was heated at 80° C. for 24 hrs. The solvents were evaporated to dryness and 20 ml of tetrahydrofuran and 20 ml of 10N NaOH was added. The mixture was stirred at room temperature for 30 minutes and the solvent was evaporated. The basic layer was acidified with concentrated HCl and extracted three times with EtOAc. The organic layers were washed with brine and dried over Na2SO4, filtered and evaporated to give the desired product as a brown powder (590 mg; 99%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C([NH:14][CH3:15])C.[C:16](#N)[CH3:17]>O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[NH:14][CH3:15])=[C:4]([CH2:16][CH3:17])[N:3]=1
Reactant: CCNC
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CC#N
Solvent: O
Product: CCc1nc(N)nc2c1ncn2NC
Temperature: 75 °C
Reaction time: 24 h

Procedure:
2-Amino-6-chloropurine (Sigma, lot #69F4064, 6.5g, 38.3 mmol) was suspended in 75mL acetonitrile. N-Ethylmethylamine (6.8 g, 115.0 mmol) was added and the reaction stirred at 75° C. for 24 hours. The solvents were evaporated to give a solid which was slurried in H2O, filtered, and air dried to yield 4.86g (25.3 mmol, 66%); mp=206°C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:42][N:43]([CH:52]=[O:53])[O:44]CC2C=CC=CC=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][C@H:25]4[CH3:31])[N:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2C(OCC2C=CC=CC=2)=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO>[CH:1]1([CH2:6][C@H:7]([CH2:42][N:43]([CH:52]=[O:53])[OH:44])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][C@H:25]4[CH3:31])[N:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@@H]1CN(C)CCN1c1cc(NC(=O)[C@@H]2CCN(C(=O)OCc3ccccc3)N2C(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)ncn1
Solvent: CO
Product: C[C@@H]1CN(C)CCN1c1cc(NC(=O)[C@@H]2CCNN2C(=O)[C@H](CC2CCCC2)CN(O)C=O)ncn1
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A mixture of phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[({6-[(2R)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinyl}amino)carbonyl]-1-pyrazolidinecarboxylate (71 mg, 0.098 mmol) and Perrlman's catalyst (13.72 mg, 0.020 mmol) in methanol (5.4 ml) was degassed and placed under 1 atm of H2 at ambient temperature. After 2 hrs, the reaction mixture was filtered and concentrated to give a residue which was purified by RP-HPLC to give (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-N-{6-[(2R)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinyl}-3-pyrazolidinecarboxamide (42 mg, 0.083 mmol, 85% yield). MS (ES+) m/z 503.2 (MH+). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.05-1.22 (m, 2H) 1.27 (d, J=6.82 Hz, 3H) 1.36-1.45 (m, 1H) 1.46-1.67 (m, 4H) 1.69-1.95 (m, 4H) 2.03 (td, J=11.94, 3.41 Hz, 1H) 2.22 (dd, J=11.62, 4.04 Hz, 2H) 2.26-2.34 (m, 3H) 2.41-2.56 (m, 1H) 2.81 (d, J=11.62 Hz, 1H) 2.85-2.98 (m, 2H) 3.10-3.27 (m, 2H) 3.49 (dd, J=14.02, 4.42 Hz, 1H) 3.59-3.84 (m, 1H) 3.84-3.99 (m, 1H) 4.17 (d, J=13.14 Hz, 1H) 4.53 (br. s., 1H) 4.61-4.72 (m, 1H) 7.41 (s, 1H) 7.86 (s, 0.7H) 8.24 (s, 1.3H).
Reaction SMILES: Br.[N:2]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].N1(C2C=C3C(=CC=2)NC(=O)CC3)CCNCC1.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][C:51]=1[O:52][CH3:53])[C:46](Cl)=[O:47]>CN(C)C=O.C(N(CC)CC)C>[CH3:41][O:42][C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][C:51]=1[O:52][CH3:53])[C:46]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH2:3][CH2:4]1)=[O:47]
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
6-(1-Piperazinyl)-3,4-dihydrocarbostyril monohydrobromide (3.5 g) was suspended in 40 ml of dimethylformamide (hereafter referred to as DMF for brevity). After adding 960 mg of sodium hydrogencarbonate, the suspension was stirred at room temperature for 30 minutes to convert the starting compound to 6-(1-piperazinyl)-3,4-dihydrocarbostyril. Then, to the mixture was added 2.34 ml of triethylamine and the mixture was stirred at room temperature while slowly adding dropwise 10 ml of DMF solution containing 2.9 g of 3,4-dimethoxybenzoyl chloride. After completion of addition the reaction mixture was stirred for 30 minutes. The reaction mixture was poured into a large amount of saturated saline solution and extracted with chloroform. The extract was washed with saturated sodium hydrogen carbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from chloroform-ethanol to give 3.8 g of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 238°-239.5° C., colorless granules.
Reaction SMILES: [Cl:1][C:2]1[N:14]=[CH:13][C:5]2[N:6]([CH3:12])[C:7](=[O:11])O[C:9](=[O:10])[C:4]=2[CH:3]=1.ClC1C=[C:18](C(NC)=CN=1)[C:19]([OH:21])=[O:20].[C:27](Cl)(Cl)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:13][N:14]=1)[N:6]([CH3:12])[C:7](=[O:11])[C:18]([C:19]([O:21][CH3:27])=[O:20])=[C:9]2[OH:10]
Reactant: O=C(Cl)Cl
Reactant: CNc1cnc(Cl)cc1C(=O)O
Reactant: Cn1c(=O)oc(=O)c2cc(Cl)ncc21
Product: COC(=O)c1c(O)c2cc(Cl)ncc2n(C)c1=O

Procedure:
6-Chloro-1-methyl-1H-pyrido[3,4-d][1,3]oxazine-2,4-dione. The title compound was prepared analogously to method 6(b) from 2-chloro-5-(methylamino)isonicotinic acid and phosgene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:22])[CH2:11][C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[O:13])=[CH:4][CH:3]=1.[C:23]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:22])[CH:11]([CH3:23])[C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc(C(=O)CC(=O)CCc2ccc(F)cc2)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC(C(=O)CCc1ccc(F)cc1)C(=O)c1cccc(C#N)c1
Temperature: 60 °C
Yield: 60.1 %

Procedure:
A mixture of 3-[5-(4-fluorophenyl)-3-oxo-pentanoyl]-benzonitrile (Example 6 Step 1) (1.0 g, 3.39 mmol), K2CO3 (469 mg, 3.39 mmol), MeI (264 μL, 4.23 mmol) and acetone (25 mL) was heated at 60° C. for 36 hours and then concentrated under reduced pressure. The residue was partitioned between H2O (20 mL) and Et2O (80 mL) and acidified to pH=3 using 2 M HCl solution. The organics were separated and concentrated under reduced pressure. The residue was purified by column chromatography on silica using 30% EtOAc/iso-hexanes to yield the alkylated product (0.63 g, 60%). 1H NMR (CDCl3, 360 MHz) δ 8.14 (1H, s), 8.04 (1H, d, J=8.0 Hz), 7.83 (1H, d, J=7.7 Hz), 7.57 (1H, J=7.8 Hz), 7.08-7.00 (2H, m), 6.87 (2H, t, J=8.6 Hz), 4.38 (1H, q, J=7.0 Hz), 2.85-2.70 (4H, m), 1.43 (3H, d, J=7.0 Hz). MS (ES−) C19H16FNO2 requires: 309, found: 308 (M+H+, 100%).
Reaction SMILES: [C:1]([CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][C:7]#[N:8])(OC)=[O:2].[BH4-].[Na+].Cl>C(COC)OC.CCOCC>[OH:2][CH2:1][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][C:7]#[N:8]
Reactant: COC(=O)C(CC#N)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: N#CCC(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
β-(Carbomethoxy)-β-phenylpropionitrile (144 g, 0.76 mol) is dissolved in dimethoxyethane (1500 mL) and NaBH4 (63.5 g, 1.67 mol) is cautiously added. The reaction mixture is stirred for 30 minutes and then heated at reflux for 2 hours. After this time the resulting solution is allowed to cool to ambient temperature and is poured onto ice. The mixture is then treated with 2N HCl (1500 mL) and is subsequently diluted with Et2O (1500 mL). The organic phase is washed with H2O (1×1000 mL), saturated NaCl solution (2×1000 mL), dried over MgSO4 and concentrated in vacuo to yield β-(hydroxymethyl)-β-phenylpropionitrile.
Reaction SMILES: COC(=O)C=CC1C2N(C3C=CC=CC=3)C=[N:11][C:10]=2C=C(C(F)(F)F)C=1.CN1[CH2:32][CH2:31][N:30]([C:33](=[O:55])[CH:34]=[CH:35][C:36]2[C:44]3[N:43]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH:42]=[N:41][C:40]=3[CH:39]=[C:38]([C:51]([F:54])([F:53])[F:52])[CH:37]=2)[CH2:29]C1>>[C:10]([CH2:32][CH2:31][N:30]([CH3:29])[C:33](=[O:55])[CH:34]=[CH:35][C:36]1[C:44]2[N:43]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:42]=[N:41][C:40]=2[CH:39]=[C:38]([C:51]([F:54])([F:52])[F:53])[CH:37]=1)#[N:11]
Reactant: COC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Reactant: CN1CCN(C(=O)C=Cc2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)CC1
Product: CN(CCC#N)C(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Yield: 5 %

Procedure:
This was prepared from 3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methyl ester in a similar manner to 1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one. The oily residue was purified by preparative LCMS to afford the title compound as a white solid (5.6 mg, 5%), m/z 399.0 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19]([CH3:21])=O>>[CH:19]([O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH3:21])[CH3:18]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(=NOC(C)C)C(C)=O

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 30 g.), iso-propyl iodode (32.5 g.), potassium carbonate (39.5 g.) and acetone (150 ml.) were treated in a similar manner to that of Example D-(1) to give ethyl 2-iso-propoxyimino-3-oxobutyrate (syn isomer, 35.4 g.), oil.
Reaction SMILES: [N:1]([CH2:4][CH:5]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH:5]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NC(CN=[N+]=[N-])CNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CN)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of benzyl tert-butyl (3-azidopropane-1,2-diyl)biscarbamate (1.3 g, 5.4 mmol) in methanol (40 mL) was added palladium on carbon (0.13 g, 10% w/w). The mixture was stirred under a hydrogen atmosphere at room temperature. After 14 hours, the reaction mixture was filtered through CELITE, and the filtrate was concentrated under reduced pressure to give benzyl tert-butyl (3-aminopropane-1,2-diyl)biscarbamate. MS ESI calc'd. for C16H26N3O4 [M+H]+ 324. found 324. 1H NMR (400 MHz, CD3OD) 7.28-7.24 (m, 5H), 5.02 (s, 2H), 3.81-3.75 (m, 1H), 3.50-3.42 (m, 2H), 2.68-2.55 (m, 2H), 1.39 (s, 9H).