Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Cl:12][C:13]1[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25]CO)[CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1.[Na]>C1(C)C=CC=CC=1>[C:1]([O:10][CH2:11][CH2:25][N:22]1[CH2:21][CH2:20][N:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=2)[CH2:24][CH2:23]1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4]
Reactant: COC(=O)c1ccccc1N
Reactant: OCCN1CCN(c2cccc(Cl)c2)CC1
Agent: [Na]
Solvent: Cc1ccccc1
Product: Nc1ccccc1C(=O)OCCN1CCN(c2cccc(Cl)c2)CC1
Yield: 72 %

Procedure:
10.6 G. (0.07 mol) of methyl anthranilate, 12.1 g. (0.05 mol) of 2-(4-m-chlorophenylpiperazino)-ethanol, 150 ml. of dry toluene and 0.09 g. of sodium are heated in a distillation apparatus for 2 1/2 hours on an oil bath, while slowly distilling the methanol eliminated in the transesterification reaction. The toluene solution is filtered while hot to remove a small amount of insoluble matter, the toluene is evaporated from the filtrate, and the residue is triturated in petroleum ether, filtered and recrystallised from isopropyl alcohol to give 13 g. (yield = 72%) of 2-(4-m-chlorophenylpiperazino)-ethyl anthranilate, which melts at 77°C., and which is found to be identical to the product prepared in Example 18 using a mixed melting point.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH:26][CH:27]([C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:40])[CH3:39])[CH:34]=[CH:35][CH:36]=1)[CH2:28][NH:29][CH3:30].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:38]([NH:37][C:33]1[CH:32]=[C:31]([CH:27]([OH:26])[CH2:28][N:29]([CH2:20][C:18]2[S:19][C:12]3[C:11](=[O:23])[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=3[C:17]=2[CH3:22])[CH3:30])[CH:36]=[CH:35][CH:34]=1)(=[O:40])[CH3:39]
Reactant: CNCC(O)c1cccc(NC(C)=O)c1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(C(O)CN(C)Cc2sc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn(C)c3c2C)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 43.7 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), N-{3-[1-hydroxy-2-(methylamino)ethyl]phenyl}acetamide (Preparation 45) (79 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 6 hours at that temperature. After cooling to room temperature, the solution was concentrated under high vacuum. The oil residue was purified with a silica gel chromatotron plate to give the title compound (62 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][NH:6][CH2:7][P:8]([OH:11])([OH:10])=[O:9])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[C:19](=[S:21])=[O:20].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO.O>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]([C:19]([S:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:7][P:8]([OH:11])([OH:10])=[O:9])[CH3:2]
Reactant: O=C=S
Reactant: CCOC(=O)CNCP(=O)(O)O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CN(CP(=O)(O)O)C(=O)SCc1ccccc1
Temperature: 25 °C

Procedure:
To ethyl-N-phosphonomethylglycinate (197 g.; 1.0 mol.) dissolved in 600 ml. of water at 0° C. was added sodium carbonate (159 g.; 1.5 mol). The resulting mixture was stirred until the gas evolution ceased. The resulting solution was added over a period of one hour to a solution of carbonyl sulfide (66 g.; 1.1 mol.) which previously had been condensed in 600 ml. of methanol at -20° C. in an ice-acetone bath. Following the addition, carbonyl sulfide was sparged through the reaction mixture for seven hours. To the mixture was added benzylchloride (171 g.; 1.0 mol.) and the resulting mixture was allowed to gradually warm to 25° C. over a period of 16 hours. The reaction mixture was then filtered and the methanol removed from the filtrate in vacuo. The residue was acidified to pH2 by the addition of concentrated hydrochloric acid. An oil separated and was extracted into 2 liters of ethylacetate. The extract was dried over sodium sulfate and concentrated in vacuo to yield a viscous oil. The oil was dried over phosphorous pentoxide in a vacuum dessicator for 48 hours to yield ethyl-N-[(benzylthio)carbonyl]-N-(phosphonomethyl)-glycinate, monohydrate (250 g.) as a yellow glass having a melting point of 56°-58° C. and the following analysis:
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16]S(C3C=CC=CC=3)(=O)=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(O)C>O.O1CCOCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=S(=O)(Oc1ccc(-c2ccc(Br)cc2)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: Oc1ccc(-c2ccc(Br)cc2)cc1

Procedure:
One example of a way of carrying out this Step is by a standard method using sodium hydroxide to hydrolyse commercially available 4'-bromo-4-benzene-sulphonyloxybiphenyl in a mixture of water and dioxan as solvent. The colourless crystals obtained by crystallisation of the product from ethanol have a melting point of 166° C.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([N+:14]([O-:16])=[O:15])=[C:8]([O:12][CH3:13])[CH:9]=2)[NH:4]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25](Cl)=[O:26].[NH:28]([CH3:30])[CH3:29]>C1COCC1>[CH3:29][N:28]([CH3:30])[CH2:24][C:25]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([O:12][CH3:13])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=2)[CH2:11][C@H:3]1[CH3:2])=[O:26]
Reactant: CNC
Reactant: COc1cc2c(cc1[N+](=O)[O-])N[C@H](C)C2
Reactant: O=C(Cl)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN(C)C)[C@H](C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A 0° C. slurry of (2R)-2-methyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole hydrogen chloride (4.55 g, 18.60 mmol) and K2CO3 (10.28 g, 74.4 mmol) in THF (200 mL) was treated with bromoacetyl chloride (3.10 mL, 37.2 mmol). After 2 h the reaction mixture was allowed to warm to rt. A 2M Me2NH solution in THF (55.8 mL, 112 mmol) was added and the reaction mixture was stirred at rt for 18 h. The resulting thick slurry was filtered and the solids were rinsed with EtOAc. The filtrate was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain N,N-dimethyl-2-[(2R)-2-methyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-2-oxoethanamine as an orange solid (2.92 g, 54%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (d, J=6.04 Hz, 3H), 2.28 (s, 6H), 2.75 (d, J=17.03 Hz, 1H), 3.14 (d, J=14.83 Hz, 1H), 3.44 (d, J=14.65 Hz, 2H), 3.90 (s, 3H), 4.77-4.92 (m, 1H), 7.36 (s, 1H), 8.43 (s, 1H); ESIMS (M+H)+=294.01.
Reaction SMILES: FC(F)(F)C(O[IH][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[IH:13]OC(=O)C(F)(F)F)=O.[C:23]1([C:29]23[CH2:38][CH:33]4[CH2:34][CH:35]([CH2:37][C:31](C5C=CC=CC=5)([CH2:32]4)[CH2:30]2)[CH2:36]3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[I:45]I>C(Cl)Cl>[I:45][C:26]1[CH:27]=[CH:28][C:23]([C:29]23[CH2:38][CH:33]4[CH2:34][CH:35]([CH2:37][C:31]([C:11]5[CH:12]=[CH:7][C:8]([I:13])=[CH:9][CH:10]=5)([CH2:32]4)[CH2:30]2)[CH2:36]3)=[CH:24][CH:25]=1
Reactant: II
Reactant: O=C(O[IH]c1ccccc1[IH]OC(=O)C(F)(F)F)C(F)(F)F
Reactant: c1ccc(C23CC4CC(C2)CC(c2ccccc2)(C4)C3)cc1
Solvent: ClCCl
Product: Ic1ccc(C23CC4CC(C2)CC(c2ccc(I)cc2)(C4)C3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
Bis((trifluoroacetoxy)iodo)benzene (26.24 g, 0.061 mol) and 1,3-diphenyl adamantane (16.00 g, 0.055 mol) and were dissolved in 150 mL of anhydrous CH2Cl2. To this solution was added sublimed iodine (14.08 g, 0.055 mol) and the dark purple solution was stirred at room temperature under dry nitrogen for 3 h until the pink color disappeared. Most of the product precipitated out of reaction as white fine crystals. The crystals were collected by filtration and washed with minimum amount of CH2Cl2 to give 24.0 g of pure product. The filtrate was washed with dilute sodium thiosulfate solution (2×80 mL), water (1×80 mL), and dried over MgSO4. Solvent was evaporated and the residue was washed with acetone and filtered to give 2.90 g product (total yield 90%). 1H NMR (CDCl3) δ (ppm): 1.76 (s, 2H), 1.88 (s, 8H), 1.93 (s, 2H), 2.30 (s, 2H), 7.10 (d, J=8.5 Hz, 4H, aromatic), 7.6 (d, J=8.5 Hz, 4H, aromatic); 13C NMR (CDCl3): 29.33, 35.61, 37.14, 41.96, 48.52, 91.04, 127.11, 137.21, 150.05. M.p. 100-102° C.; FD-MS: m/z 540 (M+).
Reaction SMILES: [C:1]([O:4][CH:5](Cl)[CH3:6])(=[O:3])[CH3:2].[C:8]([NH:11][C:12]1[C:13]([I:28])=[C:14]([N:23]([C:25](=[O:27])[CH3:26])[CH3:24])[C:15]([I:22])=[C:16]([C:19]([O-:21])=[O:20])[C:17]=1[I:18])(=[O:10])[CH3:9].[K+].[I-].[Na+]>CN(C=O)C>[C:8]([NH:11][C:12]1[C:13]([I:28])=[C:14]([N:23]([C:25](=[O:27])[CH3:26])[CH3:24])[C:15]([I:22])=[C:16]([C:19]([O:21][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:6])=[O:20])[C:17]=1[I:18])(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: CC(=O)OC(C)Cl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(C)OC(C)=O)c(I)c(N(C)C(C)=O)c1I
Reaction time: 20 h

Procedure:
1-Chloroethyl acetate (Neuenschwander, Markus et. al., Helv. Chim. Acta, 61 (1978) 2047) (4.38 g, 35.7 mmol) in dry DMF (50 ml) is added dropwise at 50° C. to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6,-triiodobenzenecarboxylate (21.64 g, 32.5 mmol) and sodium iodide (0.26 g, 1.75 mmol) in dry DMF (320 ml). The precipitate is removed by filtration after stirring for 20 hours and the solvent is removed at reduced pressure. The residue is dissolved in chloroform (300 ml) and washed four times with a saturated sodium hydrogen carbonate solution. After drying with magnesium sulfate the solution is treated with activated carbon and the solvent is removed at reduced pressure to give the title compound:
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4](=[O:13])[N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:14][O:15][C:16]1[C:17]([NH2:22])=[CH:18][CH:19]=[CH:20][CH:21]=1.[C:23](O)(=O)C>CO>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][CH:23]=[C:3]1[C:2]([CH3:1])=[N:6][N:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:4]1=[O:13]
Reactant: CC1=NN(c2ccccc2)C(=O)C1
Reactant: CC(=O)O
Reactant: COc1ccccc1N
Solvent: CO
Product: COc1ccccc1NC=C1C(=O)N(c2ccccc2)N=C1C

Procedure:
5-Methyl-2-phenyl-2,4-dihydro-pyrazol-3-one 2 g trimethylorthoformiate (188 ml) and o-anisidin (1.29 ml) are heated swith glacial acetic acid (5 ml) to 70° C. for 2 hours. After the reaction mixture cools down, methanol is added. The precipitate is collected and recrystallized in ethylacetate.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH:30]=1)[C:3]#[N:4].[OH-:32].[Na+]>S(=O)(=O)(O)O>[CH3:1][C:2]([CH3:31])([CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:15]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:14]=2[CH:30]=1)[C:3]([NH2:4])=[O:32]
Reactant: CC(C)(C#N)CCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)(CCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1)C(N)=O
Temperature: 0 °C

Procedure:
500 mg of 2,2-dimethyl-6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanonitrile was refluxed for 2 hours in 5 ml of 80% sulfuric acid. After cooling, it was carefully added to ice water, the pH was set at 8 with sodium hydroxide solution, it was extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, and it was concentrated by evaporation in a vacuum. The residue was chromatographed on silica gel.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH:20](OCC)O)=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:38]=[C:37]([CH3:39])[N:36]([CH2:40][CH2:41][C:42]([NH2:45])([CH3:44])[CH3:43])[N:35]=2)=[CH:30][CH:29]=1.[BH4-].[Na+].CC(C)=O>C(O)C.C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH:19]([OH:25])[CH2:20][NH:45][C:42]([CH3:44])([CH3:43])[CH2:41][CH2:40][N:36]2[C:37]([CH3:39])=[N:38][C:34]([C:31]3[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:33][CH:32]=3)=[N:35]2)=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2nc(C)n(CCC(C)(C)N)n2)cc1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(O)CNC(C)(C)CCn2nc(-c3ccc(OC)cc3)nc2C)ccc1OCc1ccccc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
8.5 g of methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 4.9 g of 3-[3-(4-methoxy-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine in 100 mL ethanol are stirred for three hours at 60° C., cooled to 10° C., combined batchwise with 0.8 g of sodium borohydride and stirred for a further three hours at ambient temperature. Then 10 mL acetone are added and the mixture is stirred for one hour. It is then poured onto ice and acidified with glacial acetic acid. The ethanol is distilled off, the aqueous phase remaining is made alkaline with sodium hydroxide and extracted with ethyl acetate. The organic phases are dried with sodium sulphate and evaporated down. The residue is combined with 80 mL ethanol, acidified with 3.2 g of oxalic acid, dissolved in ethanol, and seeded. The product that crystallises out is suction filtered and washed. Yield: 8 g (69%, oxalate); m.p.=210-213° C.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:17]=[CH:16]3)=[C:6]([CH2:29][CH2:30][CH3:31])[CH:5]=1)=[S:3].Br[CH2:33][C:34](=O)[CH2:35][CH3:36].N1C=CC=CC=1>C(O)C>[CH2:35]([C:34]1[N:1]=[C:2]([C:4]2[CH:28]=[CH:27][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:17]=[CH:16]4)=[C:6]([CH2:29][CH2:30][CH3:31])[CH:5]=2)[S:3][CH:33]=1)[CH3:36]
Reactant: CCCc1cc(C(N)=S)ccc1OCCCOc1ccc2c(ccn2CC(=O)OC)c1
Reactant: CCC(=O)CBr
Solvent: c1ccncc1
Solvent: CCO
Product: CCCc1cc(-c2nc(CC)cs2)ccc1OCCCOc1ccc2c(ccn2CC(=O)OC)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 15.8 %

Procedure:
To a solution of methyl (5-{3-[4-(aminocarbonothioyl)-2-propyl-phenoxy]-propoxy}-1H-indol-1-yl)acetate (Example 52, 500 mg, 1.14 mmol) in ethanol (35 mL), was added 1-bromo-2-butanone (739 mg, 2.27 mmol) and pyridine (0.14 mL, 135 mg, 1.70 mmol). The reaction mixture was stirred for 3 h at 70° C. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (0-15% EtOAc in hexane) to give 89 mg (16%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.75-7.70 (m, 2H), 7.18-7.12 (m, 2H), 7.05 (d, 1H) 6.95-6.85 (m, 2H), 6.80 (s, 1H), 6.48 (d, 1H), 4.85 (s, 2H), 4.25-4.20 (m, 4H), 3.75 (s, 3H), 2.85 (q, 2H), 2.70-2.60 (m, 2H), 2.40-2.30 (m, 2H), 1.75-1.60 (m, 2H), 1.35 (t, 3H), 0.95 (t, 3H).
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([NH:31][CH3:32])[CH:23]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([N:31]([C:2]2([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[C:10]3[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=3)[NH:4][C:3]2=[O:12])[CH3:32])[CH:23]=1
Reactant: CNc1cc(Cl)ccc1C(=O)O
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(c1cc(Cl)ccc1C(=O)O)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reaction time: 2 h
Yield: 58.4 %

Procedure:
At room temperature, 3-Bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (800 mg, 2.16 mmol), 4-Chloro-2-methylamino-benzoic acid (400 mg, 2.16 mmol) and K2CO3 (298 mg, 2.16 mmol) were dissolved in about 8 ml DMSO. After stirred for about 2 h, the solution was poured into water to obtain the crude product. The crude product was purified by chromatography to obtain 600 mg solid rac-4-Chloro-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-methyl-amino}-benzoic acid
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[O:31][N:30]=2)=[CH:25][C:21]=1[C:22](O)=[O:23]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:22](=[O:23])[C:21]3[CH:25]=[C:26]([C:29]4[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[O:31][N:30]=4)[CH:27]=[CH:28][C:20]=3[O:19][CH3:18])[N:12]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2noc(C(F)(F)F)n2)cc1C(=O)O
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Product: COc1ccc(-c2noc(C(F)(F)F)n2)cc1C(=O)NCC(C)(C)c1coc(-c2ccc(F)cc2)n1
Yield: 36 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 2-methoxy-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (40 mg, yield 36%). 1H NMR (400 MHz, MeOD) δ 8.64-8.63 (d, J=2.3 Hz, 1H), 8.45-8.42 (t, J=5.6 Hz, 1H), 8.24-8.21 (dd, J=8.8 Hz, 2.4 Hz, 1H), 8.11-8.07 (m, 2H), 7.83 (s, 1H), 7.34-7.32 (d, J=8.8 Hz, 1H), 7.27-7.23 (t, J=8.8 Hz, 2H), 3.91 (s, 3H), 3.72-3.71 (m, 2H), 1.41 (s, 6H). MS (ESI) m/z: Calculated for C24H20F4N4O4: 504.14. found: 505.2 (M+H)+.
Reaction SMILES: [Cl:1]CC1N=C(C2CCC2)SC=1.[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Cl-:1].[C:25]1([PH+:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ClCc1csc(C2CCC2)n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: [Cl-]
Product: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4.8 g of 4-chloromethyl-2-cyclobutyl-thiazole, 7.0 g of triphenylphosphine and 125 ml of toluene was heated to reflux for 16 hr and then cooled to room temperature. The mixture was then filtered to yield 4.8 g of [(2-cyclobutyl-4-thiazolyl)methyl]=triphenylphosphonium chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])O[C:9](=O)[NH:8][C:7]=2[CH:14]=1.[CH:15]([O:18][C:19]1[CH:26]=[CH:25][C:22](C=O)=[CH:21][CH:20]=1)([CH3:17])[CH3:16].C([O-])(=O)C.[NH4+:31]>CCO>[CH:15]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:9]2[N:31]=[C:11]([OH:12])[C:6]3[C:7](=[CH:14][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:8]2)=[CH:21][CH:20]=1)([CH3:17])[CH3:16]
Reactant: CC(C)Oc1ccc(C=O)cc1
Reactant: COc1ccc2c(=O)oc(=O)[nH]c2c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: COc1ccc2c(c1)NC(c1ccc(OC(C)C)cc1)N=C2O
Temperature: 80 °C
Yield: 84.7 %

Procedure:
7-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (0.5 g, 2.59 mmol), 4-isopropoxybenzaldehyde (0.425 g, 2.59 mmol), and ammonium acetate (0.239 g, 3.11 mmol) were dissolved in EtOH (1 mL) and heated at 80° C. for 0.5 h. The solvent was removed under vacuum and the crude material was purified by silica gel chromatography using a gradient of 40-100% EtOAc in Hexanes. The product fractions were collected and concentrated under vacuum to give 2-(4-isopropoxyphenyl)-7-methoxy-1,2-dihydroquinazolin-4-ol (685 mg, 85% yield). MS: MS m/z 313.2 (M++1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.[Cl:12][C:13]1[C:22]2[C:17](=[C:18]([CH3:23])[CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([CH3:24])[CH:14]=1>>[ClH:12].[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:13]1[C:22]3[C:17](=[C:18]([CH3:23])[CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH3:24])[CH:14]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2
Reactant: Cc1ccc2[nH]c(C)cc2c1
Reactant: Cc1cc(Cl)c2cccc(C)c2n1
Product: Cc1ccc2[nH]c(C)c(-c3cc(C)nc4c(C)cccc34)c2c1
Product: Cl

Procedure:
The sub-title compound was prepared by the method of Example 15 step a, using 2,5-dimethylindole and 4-chloro-2,8-dimethylquinoline.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([N:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].Cl.[OH:25]N.C(N(CC)CC)C>C(O)=O.O.[Ni]>[CH:1](=[N:2][OH:25])[C:3]1[CH:23]=[CH:22][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([N:16]4[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: N#Cc1ccc2c(c1)ncn2-c1cccc(N2CCCCC2)c1
Reactant: NO
Agent: [Ni]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: O=CO
Product: ON=Cc1ccc2c(c1)ncn2-c1cccc(N2CCCCC2)c1
Reaction time: 3 h
Yield: 69.9 %

Procedure:
To a solution of 3a1 (3.83 g, 12.9 mmol) in a mixture of formic acid (45 ml) and water (15 ml) was added Raney Ni (2.14 g, slurry in water). The mixture was refluxed with stirring for 3 hours. After cooling the mixture was filtered through celite and the filtrate was evaporated to dryness. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate (1M). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The concentrate was eluted through a short silica gel column with ethyl acetate. Evaporation of the solvent left 5-formyl-1-(3-(1-piperidinyl)phenyl)-benzimidazole (3.86 g, 100%) as an oil. This oil was dissolved in refluxing ethanol (15 ml). Hydroxyl amine hydrochloride (2.64 g, 38.0 mmol) and triethylamine (1.70 ml) was added and reflux was continued for 5 hours. The cooled mixture was rendered basic by addition of triethylamine. Water was added and the pricipitate was filtered off, washed with water and dried to yield 3b1 (2.89 g, 70%). M.p. 213-214° C.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][CH2:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[CH:35][C:36](=[O:39])[NH:37][N:38]=2)=[CH:29][CH:28]=1)(=[O:26])=[O:25]>>[CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][CH2:23][S:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH2:34][CH2:35][C:36](=[O:39])[NH:37][N:38]=3)=[CH:31][CH:32]=2)(=[O:25])=[O:26])=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OCCOCc1ccc(OCC2CO2)cc1
Reactant: NCCCS(=O)(=O)c1ccc(-c2ccc(=O)[nH]n2)cc1
Product: CC(C)OCCOCc1ccc(OCC(O)CNCCCS(=O)(=O)c2ccc(C3=NNC(=O)CC3)cc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropylsulphonyl)phenyl]-3(2H)-pyridazinone.