Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](N(C)OC)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][Mg]Br.C1COCC1.C1(C)C=CC=CC=1>CCOCC>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:15])[CH3:20])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)C1CCN(Cc2ccccc2)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(=O)C1CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
A solution of 47.32 g 1-benzyl-N-methyl-N-methoxy-piperidine-4-carboxamide in 1.5 L anhydrous ether in a 2-L 3-neck round-bottom flask fitted with a nitrogen bubbler, an overhead stirrer, and an addition funnel was cooled with an ice-acetone bath, and was treated with 270 mL of a 1.53M solution of methylmagnesium bromide in 1:3 THF:toluene with stirring over 70 minutes. After stirring in an ice bath for additional two hours, the mixture was quenched with 15 mL EtOAc, stirred for 10 minutes, and then poured into 2 L of ice water. After adjusting the pH to 8˜9, the layers were separated. The mixture was extracted with 4×250 mL ether, the combined ether solution was washed with 300 mL each of water and saturated brine, and then dried over Na2SO4. Removal of solvent under reduced pressure gave 40.68 g of crude product. This material was purified by flash chromatography on silica gel eluting with 25%˜40% EtOAc in hexanes with 1% Et3N to give 39.533 g of the title compound as a yellowish liquid. RF: 0.20 (20% EtOAc in hexanes with 1% (v/v) Et3N). 1H NMR (500 MHz, CDCl3): δ7.32˜7.35 (m, 4H), 7.25˜7.30 (m, 1H), 3.53 (s, 2H), 2.91˜2.95 (m, 2H), 2.28˜2.34 (m, 1H), 2.16 (s, 3H), 2.01˜2.07 (m, 2H), 1.83˜1.88 (m, 2H), 1.66˜1.74 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:29]([O-])([N+]([O-])=O)=[O:30]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:29]=[O:30])[C:5]([N:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CC(C)CN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)CN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 81.3 %

Procedure:
3.4 g of 1-(2-chloroethyl)-3-isobutyl-3-D-galactopyranosylurea are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 3.0 g of 1-(2-chloroethyl)-1-nitroso-3-isobutyl-3-D-galactopyranosylurea are thereby obtained as a yellow powder.
Reaction SMILES: CS(O[CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([CH3:29])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])=[CH:15][CH:14]=1)[C:7]([O:9]CC)=O)(=O)=O.[NH2:30][C:31](N)=[S:32].S1(CCCC1)(=O)=[O:35].Cl>O>[CH3:29][C:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([CH3:22])[CH2:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:6]2[S:32][C:31](=[O:35])[NH:30][C:7]2=[O:9])=[CH:18][CH:17]=1
Reactant: O=S1(=O)CCCC1
Reactant: CCOC(=O)C(Cc1ccc(OCC(C)(C)c2ccccc2)cc1)OS(C)(=O)=O
Reactant: NC(N)=S
Agent: Cl
Solvent: O
Product: CC(C)(COc1ccc(CC2SC(=O)NC2=O)cc1)c1ccccc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
2.1 g Of ethyl 2-methanesulfonyloxy-3-[4-(2-methyl-2-phenylpropyloxy)phenyl]propionate and 0.76 g of thiourea are added to 20 ml of sulfolane, and the mixture is heated at 120° C. with stirring for one hour. After adding 10 ml of 2 N-hydrochloric acid, the mixture is heated at 100° C. for 8 hours. After cooling, water is added to the mixture, and the mixture is subjected to extraction with ether. The extract is washed with water and dried. The ether is distilled off to give 1.3 g of 5-[4-(2-methyl-2-phenylpropyloxy)benzyl]thiazolidine-2,4-dione.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]2[O:8][C@H:4]([CH2:5][CH2:6]2)[C@H:3]1[C:9]([O:11][CH3:12])=[O:10].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[CH3:22].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C.C(O)(=O)C>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:1][C@H:2]2[C@H:7]3[O:8][C@H:4]([CH2:5][CH2:6]3)[C@H:3]2[C:9]([O:11][CH3:12])=[O:10])=[CH:16][C:15]=1[CH3:22]
Reactant: COC(=O)[C@H]1[C@@H](N)[C@@H]2CC[C@H]1O2
Reactant: Cc1cc(C=O)ccc1F
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)[C@H]1[C@@H](NCc2ccc(F)c(C)c2)[C@@H]2CC[C@H]1O2
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
To a stirred solution of methyl (1R,2S,3R,4S)-3-amino-7-oxabicyclo[2.2.1]heptane-2-carboxylate (400 mg, 2.34 mmol) in methanol (8 mL) under a nitrogen atmosphere, 4-fluoro-3-methyl-benzaldehyde (0.29 mL, 2.34 mmol) was added. The mixture was stirred for 10 min, and then acetic acid (0.4 mL) was added followed by sodium cyanoborohydride (368 mg, 5.85 mmol). The resulting mixture was stirred at 25° C. for 16 h, and then poured into a mixture of saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the desired product, methyl (1R,2S,3R,4S)-3-[(4-fluoro-3-methylbenzyl)amino]-7-oxabicyclo[2.2.1]heptane-2-carboxylate (610 mg, 2.08 mmol, 80%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.40 (2H, m), 1.76 (2H, m), 2.27 (3H, d, J=2.0 Hz), 2.86 (1H, d, J=7.6 Hz), 3.16 (1H, d, J=8.4 Hz), 3.64 (1H, d, J=13.2 Hz), 3.74 (3H, s), 3.79 (1H, d, J=13.6 Hz), 4.46 (1H, d, J=5.2 Hz), 4.73 (1H, d, J=4.8 Hz), 6.92 (2H, m), 7.07 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[F:24]NS(C1C=CC=CC=1)(=O)=O>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[NH:8]2)=[CH:4][C:3]=1[F:24]
Reactant: Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Reactant: O=S(=O)(NF)c1ccccc1
Solvent: CN(C)C=O
Product: Nc1nc2[nH]c(-c3ccc(F)cc3)c(-c3ccncc3)c2cc1F
Reaction time: 48 h

Procedure:
6-Amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17) (250 mg, 0.822 mmol), N-fluorobenzenesulphonamide (259 mg, 0.822 mmol), and DMF (4 mL) were warmed to 90° C. behind an explosion shield. After 48 h, the reaction was concentrated in vacuo and the residue was purified by flash chromatography (ethyl acetate: hexane 1:1) to afford 6-Amino-5-fluoro-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (28): Mass Spectrum (CI) 323 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=O)[C:11]3[CH2:14][CH2:15][CH2:16][C:10]=3[NH:9]2)=[C:4]([F:17])[CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:12]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:17])[N:9]=[C:10]2[CH2:16][CH2:15][CH2:14][C:11]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1F)CCC2
Product: Fc1cc(Cl)ccc1-n1nc2c(c1Cl)CCC2

Procedure:
By reacting 2-(4-chloro-2-fluorophenyl)-1,4,5,6-tetrahydrocyclopentapyrazol-3(2H)-one with phosphorous oxychloride according to the procedure of Example 1(d), 3-chloro-2-(4-chloro-2-fluorophenyl)-2,4,5,6-tetrahydrocyclopentapyrazole (m.p. 102°-104° ) was obtained.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.Cl.N([O-])=O.[Na+].[N-:17]=[N+:18]=[N-].[Na+]>O>[N:8]([C:7]1[CH:9]=[CH:10][C:4]([O:3][CH:2]([F:11])[F:1])=[CH:5][CH:6]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(OC(F)F)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccc(OC(F)F)cc1
Temperature: 0 °C

Procedure:
In a 20 mL four-necked flask, 4-(difluoromethoxy)aniline (0.5 g, 3.14 mmol) and hydrochloric acid (37% in water, 0.54 ml, 6.6 mmol) were combined with water (5 ml) to give a light yellow solution. Cooled to 0° C. using an ice-bath, sodium nitrite (217 mg, 3.14 mmol) was dissolved in water (1 ml) and added carefully ensuring that the temperature did not increase above 5° C. Sodium azide (204 mg, 3.14 mmol) was dissolved in water (1 ml) and added drop-wise to the orange solution, keeping the temperature below 5° C. The reaction mixture was cooled at 0-5° C. for 1 hour and an orange emulsion was observed. The layers were separated using TBME and the organic layer was washed with brine, dried over sodium sulphate and filtered. The filtrate was concentrated under vacuum to yield 1-azido-4-(difluoromethoxy)benzene as an orange liquid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][C:19]([C:21]3[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:20])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([NH:18][C:19]([C:21]3[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=4)=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:20])=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2c(c1)CCNC2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 97.8 %

Procedure:
A total of 4 g (8 mmol) of 6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester and 6 mL (78 mmol) of trifluoroacetic acid were mixed in 60 mL of methylene chloride for 5 hrs. Methylene chloride (40 mL) was added and the organic layer was washed with 3×50 mL of saturated sodium bicarbonate followed by brine. The organic layer was dried over odium sulfate and concentrated to yield 3.1 g of solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:28]([OH:30])=O)[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:16]=2)=[O:10])=[C:4]([CH3:31])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:44][CH2:45][CH2:46][OH:47].[Cl-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:28]([NH:44][CH2:45][CH2:46][OH:47])=[O:30])[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:20][CH:19]=3)[CH:16]=2)=[O:10])=[C:4]([CH3:31])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)O)n1
Reactant: NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)NCCO)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.81 g (4 mmol) of 4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-2-carboxylic acid (Example 20A) are dissolved in 16 ml of absolute DMF, and 1.94 g (12 mmol) of N,N-carbonyldiimidazole are added. The reaction mixture is stirred at RT for 1.5 h and, after addition of 144 μl of water, stirred at RT for 10 min. Then 366 mg (6 mmol) of 2-aminoethanol are added, and the mixture is stirred at RT for 1 h. The reaction mixture is mixed with saturated sodium chloride solution and extracted twice with ethyl acetate. The combined extracts are washed once each with 10% strength citric acid, saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried with magnesium sulphate and concentrated in vacuo. The residue from evaporation is purified by chromatography on silica gel with dichloromethane/methanol as eluent.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7]([Cl:16])=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[N:11][CH:10]=[CH:9]2)=[O:4].[NH2:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([NH:23][CH3:24])=[O:22]>CO>[NH3:5].[Cl:16][C:7]1[C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:17][C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([NH:23][CH3:24])=[O:22])=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[CH:12]2
Reactant: O=C(CCl)Nc1ccc2cnccc2c1Cl
Reactant: CNC(=O)c1cccc(N)c1
Solvent: CO
Product: CNC(=O)c1cccc(NCC(=O)Nc2ccc3cnccc3c2Cl)c1
Product: N
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 2-chloro-N-(5-chloroisoquinolin-6-yl) acetamide in MeOH is added KI and the solution is heated to 60° C. for 40 minutes. The mixture is cooled to 45° C. and 3-amino-N-methylbenzamide is added and stirred at 45° C. After 2-4 hours or when TLC indicates completion of the reaction, the solvents are evaporated and the residue is taken up in EtOAc and extracted with NaHCO3 (sat). The organics are dried (Na2SO4), filtered and evaporated. Flash chromatography (SiO2, NH3(2M) in MeOH/3% MeOH/CH2Cl2) gives pure 3-(2-(5-chloroisoquinolin-6-ylamino)-2-oxoethylamino)-N-methylbenzamide.
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[CH:4]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:6]=[C:7]([F:9])[CH:8]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[C:29]2[CH3:33])[N:24]=[N:25][CH:26]=1>>[ClH:20].[F:19][CH:2]([F:1])[C:3]1[CH:4]=[C:5]([C:21]2[CH:22]=[C:23]([CH2:27][N:28]3[CH:32]=[CH:31][N:30]=[C:29]3[CH3:33])[N:24]=[N:25][CH:26]=2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: CC1(C)OB(c2cc(F)cc(C(F)F)c2)OC1(C)C
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1nccn1Cc1cc(-c2cc(F)cc(C(F)F)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=319.3 (M+H+), was prepared from 2-(3-difluoromethyl-5-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([OH:35])[C:33]#[CH:34]>N(CC)CC.C(Cl)Cl.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>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:34]#[C:33][CH2:32][OH:35])[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CC3CCOCC3)cc(I)c21
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CC3CCOCC3)cc(C#CCO)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide (0.200 g), PdCl2(PPh3)2 (0.012 g) and CuI (0.029 g) in 10 mL Et2NH and 5 mL CH2Cl2 is added propargyl alcohol (0.021 g). The mixture is allowed to stir overnight at room temperature. The solvents are evaporated and the residue is partitioned between CH2Cl2 and water. The aqueous layer is extracted with CH2Cl2 (3×). The combined organic layers are washed with brine, dried and condensed. The crude product is chromatographed (Biotage flash 40S, eluent 1% MeOH/CH2Cl2 then 2% MeOH/CH2Cl2). Fractions homogeneous by TLC are combined and concentrated. The resulting solid is recrystallized from CH2Cl2/Et2O to yield 0.114 g (66%) of the desired product as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:21][CH3:22].CC1C=CC(S(O[CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:45]([O:44][C:42]([N:39]1[CH2:40][CH2:41][CH:36]([CH2:35][CH2:34][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:20])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:8]=[N:9]3)=[CH:4][C:3]=2[O:21][CH3:22])[CH2:37][CH2:38]1)=[O:43])([CH3:48])([CH3:47])[CH3:46]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
A suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (7 g, 23 mmol), (prepared as described for the starting material in Example 12), 4-(2-(4-methylphenylsulphonyloxy)ethyl)-1-tert-butoxycarbonylpiperidine (11.4 g, 30 mmol) in DMF (70 ml) containing potassium carbonate (6.32 g, 46 mmol) was stirred at 100° C. for 3 hours. After cooling, the volatiles were removed under vacuum and the residue was partitioned between ether and water. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The solid was triturated with pentane, filtered and dried under vacuum to give 7-(2-(1-tertbutoxycarbonylpiperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (10.5 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29]([OH:31])=O)=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:34])=O>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29]([Cl:34])=[O:31])=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)O)s5)nn34)ccnc2c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)Cl)s5)nn34)ccnc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophene-2-carboxylic acid (prepared according to general method A) (0.500 g, 1.15 mmol) in dichloromethane at 0° C. was added thionyl chloride (1.26 ml, 17.3 mmol) dropwise. Three drops DMF were added and the solution was stirred at room temp for three hours. The solution was concentrated to a brown residue and taken forward without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[N:12][S:13][CH:14]=2)=[CH:6][CH:5]=1.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:16]1.C(=O)([O-])[O-].[Na+].[Na+].C(N(C(C)C)CC)(C)C.[I-].[Na+]>C(Cl)Cl.CC(CC(C)C)=O>[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([C:10]4[N:11]=[N:12][S:13][CH:14]=4)=[CH:6][CH:5]=3)[CH2:28][CH2:29]2)=[N:16]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: ClCCc1ccc(-c2csnn2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: c1ccc2c(N3CCN(CCc4ccc(-c5csnn5)cc4)CC3)nsc2c1

Procedure:
To a 100 ml round-bottomed flask equipped with condenser and N2 inlet were added 0.90 g (4 mmol) 4-(4-(2-chloroethyl)phenyl)-1,2,3-thiadiazole, 0.88 g (4 mmol) N-benzisothiazolylpiperazine, 0.84 g (8 mmol) sodium carbonate, 1.39 ml (8 mmol) diisopropylethyl amine, 2 mg sodium iodide, and 40 ml methylisobutyl ketone. The reaction was refluxed 2.5 days, cooled, filtered, and the filtrate evaporated. The residue was chromatographed on silica gel using ethyl acetate/methylene chloride as eluent to afford an oil, which was taken up in methylene chloride and precipitated by addition of ether saturated with HCl. The solid was filtered, washed with ether, dried under nitrogen, washed with acetone, and dried to afford a white solid, m.p. 257°-259° C., 1.02 g (57.4%).
Reaction SMILES: C(Cl)Cl.O[CH:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][N:7]1[C:15]2[C:10](=[C:11]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.C(N(S(F)(F)[F:36])CC)C.CO>O>[F:36][CH:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][N:7]1[C:15]2[C:10](=[C:11]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: O=C1NC(=O)C(Cc2cccc3c2ccn3CC(O)c2ccccc2)S1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=C1NC(=O)C(Cc2cccc3c2ccn3CC(F)c2ccccc2)S1
Temperature: -34 °C
Reaction time: 0.08 h
Yield: 72.7 %

Procedure:
To 10 ml of methylene chloride, there was dissolved 134 mg of 5-[1-(2-hydroxy-2-phenylethyl)indol-4-yl]methyl-2,4-thiazolidinedione prepared in Example 323 under an argon gas atmosphere and the resulting solution was then cooled to -34° C. After addition of 88 mg of diethylaminosulfur trifluoride to the solution and stirring it for 5 minutes and the solution was then stirred at room temperature for additional 30 minutes. After addition of 10 ml of methanol, the solution was poured into 50 ml of water and extracted with ethyl acetate. The resulting extract was dried over anhydrous sodium sulfate and the solvent was removed through evaporation under reduced pressure to give a crude product. The product was purified by preparatory silica gel thin layer chromatography (hexane:ethyl acetate=10:1) to give 98 mg of 5-[1-(2-fluoro-2-phenylethyl)indol-4-yl]methyl-2,4-thiazolidinedione as a yellow amorphous substance. The yield thereof was found to be 73%.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:32])[CH2:28][C:29]([OH:31])=O)=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:52][C:53]([F:70])([F:69])[C:54]1[CH:59]=[CH:58][C:57]([F:60])=[CH:56][C:55]=1[C:61]([N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)=[O:62]>CN(C=O)C.O>[C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:32])[CH2:28][C:29]([N:66]2[CH2:67][CH2:68][N:63]([C:61](=[O:62])[C:55]3[CH:56]=[C:57]([F:60])[CH:58]=[CH:59][C:54]=3[C:53]([F:70])([F:69])[F:52])[CH2:64][CH2:65]2)=[O:31])=[CH:24][CH:25]=1
Reactant: O=C(c1cc(F)ccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
HOBt (25 mg, 0.185 mmol) and DIPEA (22 mg, 0.175 mmol) were added to a stirred solution of N-biphenyl-4-yl-malonamic acid (50 mg, 0.175 mmol) in DMF (3 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (50 mg, 0.26 mmol) followed by (2-trifluoromethyl-5-fluoro-phenyl)-piperazin-1-yl-methanone hydrochloride (60 mg, 0.193 mmol) were added. The reaction mixture was stirred at room temperature overnight. Water was then added and the resulting precipitate was filtered. The solid was purified by column chromatography using silica gel 60-120 mesh and 40% ethyl acetate in hexane as eluant to afford 34 mg (38%) of N-biphenyl-4-yl-3-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 514.17M+1)+, 95.5%. 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.75 (m, 1H), 7.6 (m, 6H), 7.44 (t, 2H), 7.35 (t, 1H), 7.2 (m, 1H), 7.06 (m, 1H), 4.0 (m, 2H), 3.7 (m, 4H), 3.56 (s, 2H), 3.48 (s, 1H), 3.26 (m, 3H).