Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:13]2[CH:17]=[C:16]([NH2:18])[O:15][N:14]=2)[CH3:12])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)CCl>[C:19]([NH:27][C:28]([NH:18][C:16]1[O:15][N:14]=[C:13]([CH:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=2)[CH3:12])[CH:17]=1)=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)Cc1ccc(C(C)c2cc(N)on2)cc1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCCl
Product: CC(C)Cc1ccc(C(C)c2cc(NC(=S)NC(=O)c3ccccc3)on2)cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
This isoxazol (11.35 g) was dissolved in ethylene dichloride (200 ml) and then benzoyl isothiocyanate (11.9 ml) was added, after which the resulting mixture was stirred at 60° C. for 5 hours. The reaction mixture was concentrated under reduced pressure and a small amount of water was added, after which the resulting mixture was subjected to extraction with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was isolated by a silica gel column chromatography (hexane/ethyl acetate=2/1) and then purified by a recrystallization method from toluene, to obtain 1-benzoyl-3-{3-[1-(4-isobutyl-phenyl)-ethyl]-isoxazol-5-yl}-thiourea (4.65 g).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH2:13]([N:20]1[CH2:25][CH2:24][O:23][CH:22]([CH2:26]Cl)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[CH2:13]([N:20]1[CH2:25][CH2:24][O:23][CH:22]([CH2:26][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccccc2)CCO1
Reaction time: 6 h
Yield: 76 %

Procedure:
50.2 g of potassium phthalimide are added to 61.2 g of 4-benzyl-2-chloromethylmorpholine [Synth. Com. 10, 59 (1980)] dissolved in 150 ml of abs. dimethylformamide and the mixture is boiled under stirring for 6 hours. After cooling, the crystals are filtered, washed with dimethylformamide and then with cold water and dried to give 68.95 g (76%) of the product, m.p.: 130°-132° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1>>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH2:19][N:21]4[CH2:26][CH2:25][S:24][CH2:23][CH2:22]4)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCN(c2ccc(CN3CCCC3)cc2)CC1
Reactant: C1CSCCN1
Product: c1cc(N2CCC(CN3CCSCC3)CC2)ccc1CN1CCCC1

Procedure:
Prepared from the product of Example 16 and thiomorpholine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:20]=[CH:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:17]=2)=[O:15])[C:10]([CH3:28])([CH3:27])[CH2:9]1)=O)(C)(C)C.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[CH3:27][C:10]1([CH3:28])[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14]([C:16]1[N:20]=[CH:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:17]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ncn(-c3ccccc3)n2)C(C)(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CNCCN1C(=O)c1ncn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 4.10 g (10.6 mmol) 3,3-dimethyl-4-(1-phenyl-1H-[1,2,4]-triazole-3-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester in 20 mL DCM was added 7.00 mL (90.7 mmol) TFA and the resulting mixture was stirred at RT for 4 h. The solvent was evaporated. The residue was triturated with diethyl ether and DCM. The precipitate was filtered off, washed with diethyl ether and dried.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1.C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[CH:26]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([OH:18])=[C:9]3[C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1CNCCN1Cc1ccc(F)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(F)cc1)CC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-fluorobenzyl)piperazin-2-one (10.0 g, 48.0 mmol) and diethyl ethoxymethylenemalonate (10.9 g, 50.4 mmol) in toluene (250 mL) was heated in a sealed tube at 80° C. for 4 hours. The resultant mixture was concentrated under vacuum. The residue was dissolved in anhydrous DMF (350 mL), cooled to 0° C. under an atmosphere of nitrogen, and treated with a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 57.4 mL, 57.4 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was partitioned between ethyl acetate and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with diethyl ether, and the solid precipitated was filtered to provide the titled compound.
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3].N#N.[OH-].[Na+].[CH2:17](Cl)[CH:18]=[CH2:19]>O.CC(O)C>[CH3:12][O:11][C:1]1[CH:10]=[C:6]([CH2:7][CH:8]=[CH2:9])[CH:5]=[CH:4][C:2]=1[O:3][CH2:19][CH:18]=[CH2:17]
Reactant: C=CCCl
Reactant: C=CCc1ccc(O)c(OC)c1
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: C=CCOc1ccc(CC=C)cc1OC
Reaction time: 0.17 h
Yield: 83.1 %

Procedure:
A multi-necked round bottom flask equipped with mechanical stirrer, thermometer, reflux condenser and dropping funnel was charged with 150 g of eugenol, 400 ml of 2-propanol and a gentle flow of N2 was introduced. A 40% NaOH solution (43.9 g NaOH, 1.1 mole in 66 g H2O) was added slowly to the externally cooled reaction vessel at a rate to maintain the internal temperature below 35° C. The mixture was stirred for 10 minutes and 113 ml (1.38 mole) of allyl chloride was added to the flask and heated to maintain a gentle reflux for 1 hour, at which time the reaction was complete (GC analysis). The flask was charged with 300 ml water. A Dean-Stark Trap and steam bath were used to azeotropically remove the 2-propanol. The distillation ceased when the temperature reached 94° C. and after cooling, 300 ml of hexane was added and the water layer separated. The organic layer was washed with water until the pH of the water wash was neutral, the layer was then dried over MgSO4, filtered and the solvent removed under vacuum. The product was vacuum distilled to yield 155 g (84%) of a pale yellow 3-[2-methoxy-4-(2-propenyl)phenoxy]propene.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH2:9][OH:10])[CH:3]=1.N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][Si:20]([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21])[N:5]=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(Br)cc(CO)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1nc(Br)cc(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.1 %

Procedure:
To an ice cold solution of (6-bromo-2-methylpyrimidin-4-yl)methanol (4.10 g, 20.2 mmol, Preparation #4) in DMF (40 mL) were added imidazole (5.50 g, 80.8 mmol, Spectrochem) and TBDMS-Cl (6.10 g, 40.4 mmol, Spectrochem). The resulting reaction mixture was warmed to RT and stirred about 5 h. The mixture was diluted with ice cold water (200 mL), the product was extracted with diethyl ether (3×200 mL) and washed with water (1×100 mL) and brine solution (1×150 mL). The organic layer was dried over sodium sulphate and concentrated in vacuum. The resulting crude material was purified by silica gel chromatography using 10 to 20% of EtOAc in hexane as the eluent. Relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford 4-bromo-6-((tert-butyldimethylsilyloxy) methyl)-2-methylpyrimidine 5.9 g (93%). 1H NMR (400 MHz, CDCl3) δ: 7.54 (s, 1H), 4.72 (s, 2H), 2.67 (s, 3H), 0.96 (s, 9H), 0.13 (s, 6H); MS m/z: 319.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:22][CH2:23][OH:24]>O>[OH:24][CH2:23][CH2:22][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCO)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
12.2 g (0.1 mol) of 4-hydroxybenzaldehyde, 16.6 g (0.12 mol) of potassium carbonate and 100 ml of N,N-dimethylformamide were put in a three-neck 300 ml-flask equipped with a thermometer and a stirrer and heated up to 60° C. To this mixture was dropwise added 25.0 g (0.2 mol) of 2-bromoethanol. The internal temperature rose up to 80° C. due to the reaction heat. Afterwards, the reaction system was heated and stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The resulting extract was dried with anhydrous sodium sulfate, and ethyl acetate was removed therefrom by distillation. The residue was subjected to silica gel column chromatography (using an eluent of ethyl acetate/n-hexane of 1/1) to obtain the intended 4-(2-hydroxyethoxy)benzaldehyde as an oily product. The yield of the product was 5.8 g (34.9%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][C@@H:11]([CH3:14])[CH2:12][OH:13])[N:5]=[C:4]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:3]=1.[OH-].[Na+].Cl[C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26]>CCOC(C)=O.O>[Cl:30][C:29]([Cl:32])([Cl:31])[CH2:28][O:27][C:25](=[O:26])[NH:1][C:2]1[N:6]([C:7]2[CH:17]=[CH:16][CH:15]=[C:9]([O:10][C@@H:11]([CH3:14])[CH2:12][OH:13])[CH:8]=2)[N:5]=[C:4]([C:18]([CH3:20])([CH3:19])[CH3:21])[CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: C[C@@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 108.5 %

Procedure:
A solution of Intermediate 152b (69 mg, 0.24 mmol) in EtOAc (1.2 mL) was treated with aqueous 1N NaOH (0.4 mL, 0.43 mmol) then 2,2,2-trichloroethyl chloroformate (0.034 mL, 0.25 mmol) and the mixture was stirred at RT for 2.5 h. The mixture was treated with another portion of 2,2,2-trichloroethyl chloroformate (0.010 mL, 0.07 mmol) and stirred at RT for a further 0.75 h. The mixture was diluted with EtOAc and water and the phases were separated. The aqueous layer was extracted with EtOAc (×2) and the combined organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo to give a pale red gum (121 mg). The gum was purified by FCC, using 0-40% EtOAc in cyclohexane, to give the title compound as a pale golden gum (62 mg, 56%). LCMS (Method 3): Rt 4.15 min, m/z 464.2, 466.2 [MH+].
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][NH:6][C:7](=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[C:27]([CH3:29])[C:26](Br)=[C:25]([CH3:31])[CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[CH3:31][C:25]1[CH:24]=[C:23]([O:22][CH:14]([C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:33])=[O:32])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:20])([F:21])[F:19])[CH:28]=[C:27]([CH3:29])[C:26]=1[C:39]1[CH:40]=[CH:41][C:36]([C:35]([F:46])([F:45])[F:34])=[CH:37][CH:38]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2cc(C)c(Br)c(C)c2)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Cc1cc(OC(CCCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. MS: 580.3 [M−H]−.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C(O)C>[Pd].O1CCCC1>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To 2.00 g of 1-methylsulfonyl-6-nitroindoline and a mixed solvent of 100 ml of ethanol and 100 ml of tetrahydrofuran was added 300 mg of 10% palladium/carbon under an argon atmosphere, followed by 3 hours of stirring at room temperature under a hydrogen atmosphere. The reaction solution was filtrated through celite and the organic solvent in the filtrate was removed under reduced pressure. To the residue was added 200 ml of a mixed solution of methanol, ethyl acetate, and tetrahydrofuran. Under an argon atmosphere, 1 g of 10% palladium/carbon was added and the whole was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was filtrated through celite and the organic solvent in the filtrate was removed under reduced pressure to obtain 1.66 g of 1-methylsulfonyl-6-aminoindoline as a pale yellow solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH3:15])[C:4]([NH:6][O:7]CC1C=CC=CC=1)=[O:5].[F:16][C:17]1[CH:22]=[C:21]([CH:23]([CH3:27])[C:24]([OH:26])=O)[CH:20]=[CH:19][C:18]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[F:16][C:17]1[CH:22]=[C:21]([CH:23]([CH3:27])[C:24]([NH:2][C@H:3]([CH3:15])[C:4]([NH:6][OH:7])=[O:5])=[O:26])[CH:20]=[CH:19][C:18]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Reactant: C[C@@H](N)C(=O)NOCc1ccccc1
Agent: Cl
Product: CC(C(=O)N[C@H](C)C(=O)NO)c1ccc(-c2ccccc2)c(F)c1

Procedure:
This compound was synthesized by coupling 2-amino-N-benzyloxy-(R)-propionamide HCl salt 42b with (R/S)-2-fluoro-α-methyl-4-biphenylacetic acid (flurbiprofen, Sigma) followed by hydrogenation using the procedures as described in Example 42. MS (ESI): (M−H)−=329.0.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH2:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:27][Si:28]([CH:31](Br)[C:32]#[CH:33])([CH3:30])[CH3:29]>O1CCCC1>[CH2:19]([C:20]([CH3:26])([CH2:33][C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#CC(Br)[Si](C)(C)C
Reactant: CCOC(=O)C(C)Cc1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CC#C[Si](C)(C)C)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.2 ml (1.58 gm) of diisopropylamine in 20 ml of dry tetrahydrofuran, was added dropwise a solution of n-butyllithium (9.7 ml, 1.6M) at 0° C. The solution was stirred at 0° C. for 30 min, then cooled to -78° C. A solution of 2.5 gm of ethyl 3-phenyl-2-methylpropionate in 10 ml of dry tetrahydrofuran was added. After 30 min., 3 gm of trimethylsilylpropargyl bromide in 10 ml dry tetrahydrofuran was added. The mixture was warmed up to 0° C. slowly and maintained at 0° C. for 1.75 hours. The reaction mixture was quenched with 5% hydrochloric acid and partitioned between ether and 5% hydrochloric acid. The ethereal layer, washed with brine solution and water was dried and evaporated in an oil. The oil was chromatographed on silica gel (5% ethyl acetate; petroleum ether). This procedure yielded the title compound, IR: 2170, 1738 cm-1.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]([CH3:21])[C:3]1=[O:22].[N:23]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([N:36]([CH3:38])[CH3:37])=[CH:28][CH:27]=1)=[C:24]=[S:25]>ClC(Cl)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:5]2[N:4]([CH3:21])[C:3](=[O:22])[CH:2]([NH:1][C:24]([NH:23][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]([N:36]([CH3:38])[CH3:37])=[CH:28][CH:27]=3)=[S:25])[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[C:6]=2[CH:16]=1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: CN(C)c1ccc(N=C=S)c2ccccc12
Solvent: CC(Cl)Cl
Product: CN(C)c1ccc(NC(=S)NC2N=C(c3ccccc3Cl)c3cc(Cl)ccc3N(C)C2=O)c2ccccc12
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a solution of 3-amino-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (INTERMEDIATE 8) (0.03 g, 1 mmol) in dichloroethane (5 ml) was added 4-isothiocyanato-N,N-dimethyl-1-naphthalenamine (0.025 g, 1 mmol). The reaction mixture was stirred at 70° C. for 4 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (35 mg, 60%). 1H-NMR (CDCl3): δ 8.26 (d, J=8.4 Hz, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.93 (br s, 1H), 7.73-7.06 (m, 11H) 6.10 (d, J=7.6 Hz, 1H), 3.40 (s, 3H) and 2.92 (s, 6H). MS (ESI) (M+H)+=562.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:18]2[CH:17]=[C:16]3[C:8]([C:9]4[CH:10]=[C:11]5[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][C:19]([CH3:26])([CH3:25])[C:12]5=[CH:13][C:14]=4[CH2:15]3)=[CH:7][C:6]=2[C:5]([CH3:28])([CH3:27])[CH2:4][CH2:3]1.CCCCCC.[Li]CCCC.[C:41]1([C:47]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[C:48]2[CH:52]=[CH:51][CH:50]=[CH:49]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[CH:48]1([C:47]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:20]2[CH2:21][C:22]([CH3:24])([CH3:23])[C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][C:12]=3[C:19]2([CH3:26])[CH3:25])[CH2:15][C:16]2[CH:17]=[C:18]3[C:2]([CH3:29])([CH3:1])[CH2:3][CH2:4][C:5]([CH3:28])([CH3:27])[C:6]3=[CH:7][C:8]4=2)[CH:49]=[CH:50][CH:51]=[CH:52]1
Reactant: C1=CC(=C(c2ccccc2)c2ccccc2)C=C1
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CCC2(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CC(C(c1ccccc1)(c1ccccc1)C1C=CC=C1)C2(C)C
Temperature: 1 °C
Yield: 79 %

Procedure:
In a 200 ml three-necked flask purged with nitrogen, 2.64 g (6.83 mmol, 1 eq) of 1,1,4,4,7,7,10,10-octamethyl-1,2,3,4,7,8,9,10-octahydrodibenzo(b,h)-fluorene was placed at room temperature. Then, 40 ml of dehydrated THF was added, and the mixture was stirred by a magnetic stirrer to give a solution. The solution was cooled with an ice bath (light yellow solution). To the solution, 4.6 ml (7.50 mmol, 1.10 eq) of a hexane solution of n-BuLi was dropwise added over a period of 10 minutes. Then, the ice bath was removed, and the solution was stirred at room temperature for 23 hours (dark red solution). The solution was cooled to 1° C. with an ice bath, and to the solution, a solution of 2.06 (8.94 mmol, 1.31 eq) of 6,6-diphenylfulvene in 20 ml of dehydrated THF was dropwise added over a period of 20 minutes (dark red slurry). The ice bath was removed, and the solution was stirred at room temperature for 65 hours. The resulting dark reddish brown solution was poured into 100 ml of a diluted hydrochloric acid solution to perform quenching. From the aqueous layer, the soluble component was extracted with diethyl ether, and the organic phase was washed with 100 ml of a saturated saline solution. The dispensed organic phase was dried over MgSO4, then the MgSO4 was filtered off, and from the filtrate the solvent was vacuum distilled off by a rotary evaporator to obtain an orangy yellow amorphous product. The amorphous product was washed with methanol, then filtered and dried in a vacuum disiccator to obtain 3.31 g of a slightly yellow powder (yield: 79%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.Cl.[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:29]([F:32])([F:31])[F:30])=[C:22]([C@H:24]2[CH2:28][CH2:27][CH2:26][NH:25]2)[CH:23]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:29]([F:32])([F:30])[F:31])=[C:22]([C@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)[CH:23]=1
Reactant: Fc1ccc(C(F)(F)F)c([C@H]2CCCN2)c1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3C(F)(F)F)nc12
Temperature: 120 °C
Yield: 96.4 %

Procedure:
Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, 0.51 g, 2.26 mmol), (R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidine hydrochloride (0.610 g, 2.26 mmol) and diisopropylethylamine (1.12 mL, 6.78 mmol) were suspended in isopropanol (2.5 mL) and heated to 120° C. for 24 hours. The reaction mixture was purified by reverse phase chromatography eluting with 0-75% acetonitrile/water to yield the title compound (0.92 g, 96.4% yield). MS (apci) m/z=423.0.0 (M+H).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]2[N:11]([CH3:49])[C:12]([CH2:14][O:15][C:16]3[CH:48]=[CH:47][C:19]([CH2:20][CH:21]4[S:25][C:24](=[O:26])[N:23](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:22]4=[O:46])=[CH:18][CH:17]=3)=[N:13][C:8]2=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(O)(=O)C>O>[CH:1]([O:4][C:5]1[N:10]=[C:9]2[N:11]([CH3:49])[C:12]([CH2:14][O:15][C:16]3[CH:48]=[CH:47][C:19]([CH2:20][CH:21]4[S:25][C:24](=[O:26])[NH:23][C:22]4=[O:46])=[CH:18][CH:17]=3)=[N:13][C:8]2=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc2nc(COc3ccc(CC4SC(=O)N(C(c5ccccc5)(c5ccccc5)c5ccccc5)C4=O)cc3)n(C)c2n1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Oc1ccc2nc(COc3ccc(CC4SC(=O)NC4=O)cc3)n(C)c2n1
Yield: 80.4 %

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 0.78 g of 5-{4-(5-isopropoxy-3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 103) was treated with 12 ml of a 3:1 by volume mixture of acetic acid and water. After working up the product as described in Example 12, the resulting crude product was crystallized by trituration with ethyl acetate, to give 0.40 g of the title compound, melting at 210°-212° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-])=O)[CH:8]=2)[NH:3]1>CO.[Pd]>[NH2:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])([CH3:16])[C:11](=[O:12])[NH:10]2
Reactant: CC1(C)Nc2ccc([N+](=O)[O-])cc2NC1=O
Agent: [Pd]
Solvent: CO
Product: CC1(C)Nc2ccc(N)cc2NC1=O

Procedure:
A solution of 1,2-dihydro-2,2-dimethyl 6-nitro 3-(4H)-quinoxalinone(663 mg, 3 mmol) in CH3OH (10 ml) is hydrogenated with 50 psi H2 (g) at room temperature in the presence of a catalyst of 10% by weight palladium on charcoal (50 mg). After the starting material is consumed, the solution is filtered and concentrated in vacuo to yield 6-amino-1,2-dihydro-2,2-dimethyl-3-(4H)-quinoxalinone.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:15](/[N:17]=[CH:18]\[N:19](C)C)=O)=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1.C(O)(=O)C.O.[NH2:27]N>>[Br:1][C:2]1[S:3][C:4]([C:15]2[NH:17][CH:18]=[N:19][N:27]=2)=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1
Reactant: CN(C)/C=N\C(=O)c1sc(Br)nc1Cc1ccc(Cl)cc1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(Cc2nc(Br)sc2-c2nnc[nH]2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In a 250 mL round bottomed flask were placed 2-bromo-4-(4-chlorobenzyl)-N-[(1Z)-(dimethylamino)methylene]-1,3-thiazole-5-carboxamide and acetic acid (50 mL, 900 mmol). Hydrazine hydrate (490 uL, 10 mmol) was added and the mixture was stirred for 1 h at 50° C. The mixture was allowed to cool to rt, then was concentrated under reduced pressure to obtain 3-[2-bromo-4-(4-chlorobenzyl)-1,3-thiazol-5-yl]-4H-1,2,4-triazole as a yellowish off-white crystalline solid. The crude material was used in the next step without further purification. LC/MS (FA) ES+ 357.