Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH2:30][OH:31])[C:3]([C@H]1CCN(C2C=CC(N3C[C@H](CNC4C=CON=4)OC3=O)=CC=2F)C1)=[O:4].Cl.[NH:33]1[CH2:38][CH2:37][C:36]([C:39]2[C:44]([F:45])=[CH:43][C:42]([N:46]3[CH2:50][C@H:49]([CH2:51][N:52]([C:60]4[CH:64]=[N:63][S:62][N:61]=4)C(OC(C)(C)C)=O)[O:48][C:47]3=[O:65])=[CH:41][C:40]=2[F:66])=[CH:35][CH2:34]1>>[OH:1][C@@H:2]([CH2:30][OH:31])[C:3]([N:33]1[CH2:38][CH2:37][C:36]([C:39]2[C:40]([F:66])=[CH:41][C:42]([N:46]3[CH2:50][C@H:49]([CH2:51][NH:52][C:60]4[CH:64]=[N:63][S:62][N:61]=4)[O:48][C:47]3=[O:65])=[CH:43][C:44]=2[F:45])=[CH:35][CH2:34]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CN(c2cc(F)c(C3=CCNCC3)c(F)c2)C(=O)O1)c1cnsn1
Reactant: O=C([C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1)[C@@H](O)CO
Agent: Cl
Product: O=C([C@@H](O)CO)N1CC=C(c2c(F)cc(N3C[C@H](CNc4cnsn4)OC3=O)cc2F)CC1
Yield: 71 %

Procedure:
Using the method described for the appropriate intermediate of Example 17, apart from routine changes in the eluant used for chromatography, and starting from 3-(4-(1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)-(N-(t-butoxycarbonyl)-1,2,5-thiadiazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride (800 mg, 1.51 mM, see Example 25), gave the title product (669 mg, 71%). NMR (DMSO-d6) δ: 1.29 (s, 3H); 1.32 (s, 3H); 1.52 (s, 9H); 2.30 (m, 1H); 2.40 (m, 1H); 3.68 (m, 2H); 3.90 (dd, 1H); 4.04-4.28 (m, 4H); 4.37 (m, 1H); 4.90 (m, 1H); 5.06 (m, 1H); 5.72 (m, 2H); 5.88 (m, 1H); 7.31 (d, 2H); 8.96 (s, 1H). MS (ESP): 622 (MH+) for C28H33F2N5O7S
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]#[CH:24])[CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:24]#[C:23][C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=2)[NH2:16])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C#Cc1cccc(N)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Nc1cccc(C#Cc2ccc(F)cc2)c1
Temperature: 65 °C
Yield: 96.4 %

Procedure:
A multinecked flask as described in Example 1 was charged with 50.0 g (0.28 mol) of p-bromofluorobenzene, 200 ml of dried, degassed triethylamine, 35.0 g (0.30 mol) of 3-aminophenylacetylene, 0.23 g (0.29 mmol) of bis(triphenyl phosphine) palladium II chloride, 1.03 g (3.92 mmol) of triphenylphosphine, and 0.1 g (0.52 mmol) of cuprous iodide. The reaction mixture was heated at 65° C. for 48 hours at which point gas chromatography showed the reaction to be complete. The mixture was cooled to room temperature and diluted with 200 ml of toluene. The toluene/triethylamine solution was decanted and concentrated on the rotary evaporator to give 75 g (0.27 mol, 96% yield) of the product as a bright yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:15]2[CH:16]=[N:17][N:18](CC3C=CC=CC=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].O=O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[C:14]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2cnn(Cc3ccccc3)c2)CC1
Agent: CC(C)(C)[O-]
Agent: O=O
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2cn[nH]c2)CC1
Yield: 39.3 %

Procedure:
To a solution of 4-(1-phenyl-1-(1-benzylpyrazol-4-yl)-methylene)-piperidine-1-carboxylic acid tert-butyl ester (0.079 g, 0.18 mmol) in DMSO (0.2 mL) was added potassium tert-butoxide solution (1 M in THF, 2.0 mL, 2.0 mmol) and O2 was bubbled through the stirring mixture for 15 min. The reaction mixture was then quenched with saturated aqueous NH4Cl (2 mL) and extracted with EtOAc (×2). The combined organic phase was dried (Na2SO4) and evaporated, and the resulting residue was purified by preparative HPLC to give the title compound (0.024 g, 39%) as a gum:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].[CH3:16][N:17]=[C:18]=[O:19]>C(Cl)Cl>[CH3:16][NH:17][C:18]([N:13]1[CH2:12][CH2:11][N:10]([C:8](=[O:9])[CH2:7][N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[CH2:15][CH2:14]1)=[O:19]
Reactant: O=C(CN1CCCC1=O)N1CCNCC1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N1CCN(C(=O)CN2CCCC2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
700 mg (3.31 mmol) of (2-oxopyrrolidin-1-yl)acetylpiperazine was dissolved in 10.5 ml of CH2Cl2, and 0.215 ml (3.64 mmol) of methyl isocyanate was added to the mixture under ice-cooling, and the mixture was warmed to room temperature and stirred for 1 hr. After evaporating CH2Cl2, the precipitated crystals were washed with Et2O and collected by filtration. By recrystallizing from EtOH-Et2O, 856 mg of the objective compound (yield: 96.3%) was obtained as colorless prisms.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[NH:16]1[CH2:21][CH2:20][S:19][CH2:18][CH2:17]1>C1C=CC=CC=1>[S:19]1[CH2:20][CH2:21][N:16]([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH2:17][CH2:18]1
Reactant: COC(=O)CCCI
Reactant: C1CSCCN1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCCN1CCSCC1

Procedure:
A mixture of 64.0 g. (0.28 mole) of methyl γ-iodobutyrate, 28.0 g. (0.28 mole) of triethylamine, 28.7 g. (0.28 mole) of thiomorpholine (J. Am. Chem. Soc. 76, 1187 (1954)) and 1 liter of benzene was stirred and heated at 60°-70°C. for 18 hours. After cooling the reaction mixture, the precipitated amine hydroiodide was removed by suction filtration. The benzene solution was evaporated to give a orange-red residue which was vacuum distilled (b.p. 84°-85°C. at 0.1 mm) to give 28.38 g. (50%) of the product as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.C([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[C:29](Cl)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:21]1=[O:37])(=O)C>ClCCl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7]/[C:29](=[C:22]2\[C:21](=[O:37])[NH:20][C:28]3[C:23]\2=[CH:24][CH:25]=[CH:26][CH:27]=3)/[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccccc21
Reactant: COc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.18 g (1.5 mmol) of 4-methoxyaniline and 0.2 g (0.28 mmol) of triethylamine are dissolved in 5 ml of dichloromethane and at 5° C. combined with a solution of 0.45 g (1.5 mmol) of 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone in 10 ml of dichloromethane and then stirred for 3 hours at ambient temperature. After removal of the solvent in vacuo the residue is taken up in ethyl acetate/water. The organic phase is washed with water, dried and the solvent is eliminated in vacuo. Then the mixture is dissolved in 15 ml of methanol, combined with 3 ml of 1N sodium hydroxide solution, stirred for 3 hours at ambient temperature and diluted with water and ethyl acetate. The organic phase is dried and concentrated by evaporation. The residue is heated in ethyl acetate, cooled, then suction filtered and dried.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:17])[C:4]([C:6]1([C:13]([F:16])([F:15])[F:14])[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5].[BH4-].[Na+].O.Cl>C(O)C>[CH3:1][O:2][N:3]([CH3:17])[C:4]([C:6]1([C:13]([F:14])([F:15])[F:16])[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5]
Reactant: CON(C)C(=O)C1(C(F)(F)F)CCC(=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CON(C)C(=O)C1(C(F)(F)F)CCC(O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
18.0 g (71.1 mmol) of 4-Oxo-1-trifluoromethyl-cyclohexanecarboxylic acid methoxy-methyl-amide (68) were dissolved in 350 ml of anhydrous ethanol and 2.96 g (78.2 mmol) of NaBH4 were added portionwise at −70° C. The mixture was then stirred for 1 h at ambient temperature, followed by addition of 500 ml of water. Initially, the pH was then adjusted to pH=4-5 using a 10% aqueous HCl-solution to remove remaining NaBH4. Afterwards, the pH was adjusted to pH=8 using saturated aqueous NaHCO3-solution and the ethanol was evaporated. The residual solution was extracted three times using 300 ml of ethyl acetate each. Afterwards, the organic layer was washed using 300 ml of a saturated aqueous NaCl-solution, dried over MgSO4 and evaporated. Chromatography on silica gel using ethyl acetate/n-heptane yielded 6.00 g of 69 as a colourless oil, containing only one cis/trans isomer of unknown configuration. Rt=0.66 min (Method P).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[N:45]=[C:44]([C:46]([NH:48][CH3:49])=[O:47])[CH:43]=[CH:42][CH:41]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:40]2[N:45]=[C:44]([C:46]([NH:48][CH3:49])=[O:47])[CH:43]=[CH:42][CH:41]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CNC(=O)c1cccc(Br)n1
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CNC(=O)c1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)n1
Yield: 31.7 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (2.97 g), 6-bromo-N-methyl-2-pyridinecarboxamide (1.30 g) and tetrakis(triphenylphosphine)palladium(0) (0.110 g), the title compound (1.11 g) was obtained as colorless powder crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:4]=2[CH:3]=1.[NH2:17][NH2:18].O>C(O)C>[NH:17]([C:2]1[N:7]=[N:6][C:5]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:4]=2[CH:3]=1)[NH2:18]
Reactant: Clc1cc2c(nn1)-c1ccccc1CCC2
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1cc2c(nn1)-c1ccccc1CCC2
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A mixture of the compound of formula (Df), 3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine, (4.3 g, 18.6 mmol) and anhydrous hydrazine (11.7 mL, 370 mmol) in 45 mL of ethanol was refluxed for 16 h. After cooling to ambient temperature, 5 mL of water was added and the volatiles were then evaporated. To the solid residue was added cold water (about 80 mL). After sonication for 10 min, the resulting solid was collected by filtration and washed with cold water three times. After freeze-drying, the compound of formula (D-1), 3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine, (4.14 g, 98%) was obtained as a slight yellow solid, 1H NMR (300 MHz, CD3OD) δ: 7.59 (m, 1H), 7.39-7.26 (m, 3H), 7.04 (s, 1H), 2.54 (t, J=6.9 Hz, 2H), 2.47 (t, J=6.9 Hz, 2H), 2.18 (quant, J=6.9 Hz, 2H); LC-MS: purity: 100%; MS (m/e): 227 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:18](=[O:28])[C:19]([CH2:21][C:22]5[CH:23]=N[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH3:17])[CH:10]=3.[CH:29](=O)C1C=CC=CC=1>>[CH2:21]([C:19]1[C:18](=[O:28])[C:7]2[CH:8]=[C:9]([O:16][CH3:17])[CH:10]=[C:11]3[C:6]=2[N:5]([CH:20]=1)[C:4]1[CH:3]=[C:2]([Br:1])[CH:15]=[CH:14][C:13]=1[S:12]3)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:29][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cc2c3c(c1)c(=O)c(Cc1cccnc1)cn3-c1cc(Br)ccc1S2
Product: COc1cc2c3c(c1)c(=O)c(Cc1ccccc1)cn3-c1cc(Br)ccc1S2
Yield: 46 %

Procedure:
According to Example 1 <step 4>, the compound (3 g) produced in Example 36 <step 2> was reacted with benzaldehyde (1.25 mL) to obtain the title compound (1.73 g; 46%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH:16]3[CH2:18][CH:13]1[CH2:14][N:15]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:7][N:6]=[CH:5]2.[CH:26]1([NH:29][C:30](=[O:47])[C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:26]1([NH:29][C:30]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH:16]5[CH2:18][CH:13]3[CH2:14][N:15]5[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[N:7][N:6]=[CH:5]4)[CH:32]=2)=[O:47])[CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2c1nncc2cc(Br)ccc12
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CC4CC3CN4C(=O)OC(C)(C)C)nncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A mixture of tert-butyl 5-(6-bromophthalazin-1-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylate (0.18 g, 0.44 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.14g, 0.44 mmol), tetrakis(triphenylphosphine)palladium (25 mg, 0.022 mmol) and 2 M potassium carbonate (0.66 mL, 1.32 mmol) in 5 mL DME/EtOH (4:1) was stirred at 90° C. for 2 h. The mixture was transferred directly to a column and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 10% 2M ammonia in MeOH/DCM to give tert-butyl 5-(6-(5-(cyclopropylcarbamoyl)-2-methylphenyl) phthalazin-1-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylate (0.20 g) as a yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:31])[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:25][CH2:26][N:27]([C:30]([CH:32]2[CH2:37][CH2:36][N:35]([C:18]([C:12]3[S:13][C:14]4[CH2:15][CH2:16][O:17][C:8]5[CH:7]=[C:6]([C:4]6[CH:5]=[N:1][NH:2][CH:3]=6)[CH:22]=[CH:21][C:9]=5[C:10]=4[N:11]=3)=[O:19])[CH2:34][CH2:33]2)=[O:31])[CH2:28][CH2:29]1
Reactant: CN1CCN(C(=O)C2CCNCC2)CC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CN1CCN(C(=O)C2CCN(C(=O)c3nc4c(s3)CCOc3cc(-c5cn[nH]c5)ccc3-4)CC2)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (4-methylpiperazin-1-yl)(piperidin-4-yl)methanone (1.2 equiv) to give 205 (M+1 507.0)
Reaction SMILES: C(O)(=O)C.[OH:5][C:6]1[CH:19]=[C:18]2[C:9]([CH:10]=[CH:11][C:12]3[O:13][CH:14]=[C:15]([CH:21]=O)[C:16](=[O:20])[C:17]=32)=[CH:8][CH:7]=1.Cl.[NH2:24]O.C([O-])=O.[Na+]>C(O)=O>[OH:5][C:6]1[CH:19]=[C:18]2[C:9]([CH:10]=[CH:11][C:12]3[O:13][CH:14]=[C:15]([C:21]#[N:24])[C:16](=[O:20])[C:17]=32)=[CH:8][CH:7]=1
Reactant: NO
Reactant: O=Cc1coc2ccc3ccc(O)cc3c2c1=O
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=CO
Product: N#Cc1coc2ccc3ccc(O)cc3c2c1=O

Procedure:
A mixture of compound 5, hydroxylamine hydrochloride and sodium formate is refluxed in formic acid to provide 9-hydroxy-1-oxo-1H-naphtho[2,1-b]pyran-2-carbonitrile, Compound 8.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.C1C(=O)N([I:18])C(=O)C1.OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([I:18])=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2ccsc2n1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Product: Clc1ccc2cc(I)sc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a flask charged with 6-Chlorothieno[2,3-b]pyridine (500 mg, 3.0 mmol) and a stir bar was added NIS (800 mg, 3.5 mmol) and Triflic acid (5 mL). The mixture was monitored by TLC and allowed to stir at RT for 4 hours. The reaction was poured into ice, neutralized with aqueous sodium carbonate, extracted with DCM, dried over sodium sulfate, concentrated and purified by flash chromatography (Hex: EtOAc gradient) to obtain the title product. LC-MS (IE, m/z): 296 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH2:22][OH:23])[N:15]=1)[N:7]=3.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[N:7]1[C:8]([C:14]2[N:18]([CH:19]([CH3:20])[CH3:21])[N:17]=[C:16]([CH:22]=[O:23])[N:15]=2)=[CH:9][N:10]2[C:6]=1[C:5]1[CH:24]=[CH:25][CH:2]=[CH:3][C:4]=1[O:13][CH2:12][CH2:11]2
Reactant: CC(C)n1nc(CO)nc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)n1nc(C=O)nc1-c1cn2c(n1)-c1ccccc1OCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of [5-(8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-methanol 315 (166 mg, 0.51 mmol) in DCM (5 mL) was treated with Dess-Martin periodinane (DMP, 238 mg, 0.56 mmol) and resultant solution stirred at RT for 2 h under an atmosphere of nitrogen. The reaction was quenched by the addition of sodium thiosulphate (620 mg in 1 mL water) before the addition of further water and extracted twice with DCM. The combined organic extracts were washed with water then dried (Na2SO4), filtered and concentrated in vacuo to give 5-(4,5-Dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazole-3-carbaldehyde as a cream solid (170 mg, quantitative). LCMS: RT=4.30 min, [M+H]+ 324. 1H NMR 400 MHz (DMSO-d6) δ: 9.91 (1 H, s), 8.43 (1 H, dd, J=8.06, 1.78 Hz), 8.11 (1 H, s), 7.34-7.34 (1 H, m), 7.17-7.17 (1H, m), 7.07 (1 H, dd, J=8.17, 1.23 Hz), 6.03 (1 H, m), 4.57-4.48 (4 H, m), 1.55 (6 H, d, J=6.60 Hz)
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[CH3:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18](=O)[CH3:19])=[CH:14][CH:13]=1>>[CH3:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][CH:18]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:19])=[CH:14][CH:13]=1
Reactant: NCC(O)c1ccccc1
Reactant: CC(=O)COc1ccc(C)cc1
Product: Cc1ccc(OCC(C)NCC(O)c2ccccc2)cc1

Procedure:
The title compound was prepared in the manner described in Example 3 using 2-hydroxy-2-phenylethanamine and (4-methylphenoxy)propan-2-one. Recrystallization from heptane gave the title compound m.p. 87-105. τ(CDCL3) 8.9 (3H, d, J=6 Hz), 7.7 (3H, s), 6.7-7.5 (3H, +2H (disappears with D2O)), 6.2 (2H, m), 5.3 (1H, m), 3.3 (2H, d, J=9 Hz), 2.9 (2H, d, J=9 Hz), 2.7 (5H, m).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]2[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][Cl:27].O>CN(C=O)C>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][N:12]1[CH:13]=[C:8]([C:4]2[O:3][C:2]([CH3:1])=[N:6][C:5]=2[CH3:7])[C:9](=[O:15])[NH:10][C:11]1=[O:14]
Reactant: ClCCCCBr
Reactant: Cc1nc(C)c(-c2c[nH]c(=O)[nH]c2=O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C)c(-c2cn(CCCCCl)c(=O)[nH]c2=O)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
5-(2,4-Dimethyl-oxazol-5-yl)-1H-pyrimidine-2,4-dione (Prep61, 300 mg, 1.45 mmol) was dissolved in dry DMF (4 ml) and K2CO3 (300 mg, 2.17 mmol) was added. The mixture was stirred at room temperature for 1 h, then a solution of 1-bromo-4-chloro-butane (commercially available from Aldrich, 496 mg, 2.9 mmol) in dry DMF (1 ml) was added. After stirring the reaction at room temperature for 48 hours, water was added and the mixture was extracted with diethylether. The aqueous layer was then extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated; the crude was used without further purification in the next step (200 mg, 47% yield).
Reaction SMILES: [NH3:1].O=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]([F:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].O>C1(C)C=CC=CC=1>[NH2:1]/[C:3](/[C:11]([F:14])([F:13])[F:12])=[C:4](/[F:10])\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: N
Reactant: CCOC(=O)C(F)C(=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)/C(F)=C(\N)C(F)(F)F

Procedure:
Ammonia is introduced with stirring into a solution of 7.5 g of ethyl 3-oxo-2,4,4,4-tetrafluorobutyrate in 20 ml of toluene at 75° C. up to saturation. Then the reaction mixture is heated using a water separator for 5 hours, during which ethyl 3-amino-2,4,4,4-tetrafluorocrotonate is formed as an intermediate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:31]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:31])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(OCc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: NCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 25 h
Yield: 81 %

Procedure:
To a solution of 4-benzyloxybenzyl alcohol (3.1 g) in toluene (40 ml) were sequentially added diphenylphosphoryl azide (4.8 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.6 g), and the solution was stirred for 25 hours at room temperature. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. Obtained by purifying the residue by silica gel column chromatography (hexane-ethyl acetate system), to a solution of the resulting 1-azidomethyl-4-benzyloxybenzene (3.0 g) in tetrahydrofuran (40 ml) were sequentially added water (3 ml) and triethylphosphine (2.0 ml), and the solution was stirred for 1 hour and 10 minutes at room temperature. The reaction solution was concentrated in vacuo, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (2.5 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([O:21]C)=[O:20])=[N:4][C:5]([C:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:12][CH:13]=2)=[CH:6][N:7]=1.[OH-].[Na+].Cl>CO.O>[NH2:1][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[N:4][C:5]([C:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: CCS(=O)(=O)N1CC=C(c2cnc(N)c(C(=O)OC)n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCS(=O)(=O)N1CC=C(c2cnc(N)c(C(=O)O)n2)CC1
Temperature: 60 °C
Yield: 65 %

Procedure:
A solution of methyl 3-amino-6-(1-ethylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)pyrazine-2-carboxylate (5.5 g, 16.85 mmol) in MeOH (30 mL) was treated with a solution of NaOH (8.425 mL of 2 M, 16.85 mmol) in H2O (30 mL). The resulting mixture was heated to 60° C. for 2 hours. After this time the solution was allowed to cool, neutralised with HCl and the resultant precipitate filtered (3.6 g, 65% Yield). 1H NMR (400.0 MHz, DMSO) d 1.20 (3H, t), 2.65 (2H, br s), 3.11 (2H, q), 3.44 (2H, m), 3.94 (2H, m), 6.60 (1H, m), 7.51 (2H, br s), 7.95 (1H, s), 8.52 (1H, s) ppm; MS (ES+) 312.97