Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:34])([F:33])[C:22](B1OC(C)(C)C(C)(C)O1)=[CH2:23].C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[F:20][C:21]([F:34])([F:33])[C:22]([C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH2:23]
Reactant: C=C(B1OC(C)(C)C(C)(C)O1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=C(c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2)C(F)(F)F
Temperature: 85 °C
Reaction time: 12 h
Yield: 87.4 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (328 mg, 1.00 mmol), 1-(trifluoromethyl)vinylboronic acid pinacol ester (222 mg, 1.00 mmol), saturated aqueous sodium carbonate solution (6 ml) and tetrakis(triphenylphosphine)palladium(0) (32.6 mg, 0.0282 mmol) in dimethoxyethane (10 ml) was stirred at 85° C. for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the desired product (300 mg, 87.5%) as an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][C@@H:12]1[CH2:17][C@H:16]([CH2:18][C:19](=[O:27])[N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[O:15][C:14]([CH3:29])([CH3:28])[O:13]1)(=O)C>CO>[OH:10][CH2:11][C@H:12]1[O:13][C:14]([CH3:28])([CH3:29])[O:15][C@@H:16]([CH2:18][C:19]([N:20]([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:25])[CH3:26])=[O:27])[CH2:17]1
Reactant: CC(=O)OC[C@@H]1C[C@H](CC(=O)N(C(C)C)C(C)C)OC(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)N(C(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1)C(C)C
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (150 grams) added to a solution of 50 grams of ((4S,6R)-6-((diisopropylcarbamoyl)methyl)-2,2-dimethyl-1,3-dioxan-4-yl)methyl acetate in 250 ml methanol. Stirred the reaction mixture at 0-5° C. for 2 hours. Quenched the reaction mixture with chilled water. Stirred the reaction mixture for 20 minutes. Extracted the reaction mixture thrice with dichloromethane. Washed the organic layer with brine and water. Dried the organic layer over sodium sulfate and distilled the solvent completely under reduced pressure to get the title compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[H-].[Na+].[CH2:17]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH2:26][CH3:27])[C:20]=1[C:28]1[C:29](=[O:40])[N:30]([CH3:39])[N:31]=[C:32]([CH3:38])[C:33]=1S(C)(=O)=O)[CH3:18]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O.CS(C)=O>[CH2:17]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH2:26][CH3:27])[C:20]=1[C:28]1[C:29](=[O:40])[N:30]([CH3:39])[N:31]=[C:32]([CH3:38])[C:33]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:18]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Reactant: Oc1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Solvent: CS(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1-c1c(Oc2ccccc2)c(C)nn(C)c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29.3 %

Procedure:
To a test tube (outside diameter: 21 mm Φ×overall length: 160 mm), phenol (108 mg), toluene (930 mg), and 60% of oily sodium hydride (44 mg) were added, and stirred at room temperature for 5 minutes. To the mixture, (4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydropyridazin-3-one ((2-34)-(1)-39) (299 mg) was added, and stirred at room temperature for 1.5 hours and at 100° C. for 1.5 hours. To the mixture, benzyltriethylammonium chloride was added and stirred for 1.5 hours, and then DMSO (1.1 ml) was added and stirred for 2 hours. After the mixture was cooled to room temperature, water was added and extracted with toluene 3 times. The organic layers were combined, washed with 2N aqueous sodium hydroxide solution 3 times, and concentrated under reduced pressure. The residue was subjected to column chromatography (hexane: ethyl acetate=3:1) to give 91 mg of 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-phenoxy-2,3-dihydro-3-pyridazinone ((1-31)-(1)-39).
Reaction SMILES: C(=O)=O.CC(C)=O.[Cl:8][C:9]1[CH:37]=[CH:36][C:12]2[N:13]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:14](=[O:26])[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:11]=2[CH:10]=1.CC([O-])(C)C.[K+].[Br:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[CH2:48]Br>C1COCC1>[Br:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[CH2:48][CH:15]1[C:14](=[O:26])[N:13]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:12]2[CH:36]=[CH:37][C:9]([Cl:8])=[CH:10][C:11]=2[C:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:16]1
Reactant: BrCc1cccc(Br)c1
Reactant: COc1ccc(CN2C(=O)CN=C(c3ccc(OC)cc3)c3cc(Cl)ccc32)cc1
Agent: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(Cc3cccc(Br)c3)N=C(c3ccc(OC)cc3)c3cc(Cl)ccc32)cc1
Yield: 84.5 %

Procedure:
To a stirred and cooled (dry ice/acetone bath) solution of E2 (6.00 g, 14.2 mmol) in THF (80 mL) was slowly added 1 M KOtBu (21 mL, 21 mmol, 1.5 eq). The resulting deep red mixture was stirred over dry ice/acetone bath ˜10 min followed by the slow addition of a solution of 3-bromobenzyl bromide (5.10 g, 21.4 mmol, 1.5 eq) in THF (15 mL). After stirring another ˜45 min at −78° C., the reaction mixture was quenched with saturated brine and diluted with EtOAc. The organic layer was dried (Na2SO4), filtered and evaporated (rotovap, then high vacuum). Chromatography over silica gel using 10-30% EtOAc/heptane gave 7.08 g (yield of 84%) of the title product. Noting that when using benzyl chlorides as alkylating agents, tetrabutyl ammonium iodide was added along with the alkylating agent at low temperature. 1H NMR (300 MHz, CDCl3) δ 3.57 (d, 2H), 3.70 (s, 3H), 3.73 (t, 1H), 3.83 (s, 3H), 4.59 (d, 1H), 5.62 (d, 1H), 6.61 (d, 2H), 6.8-6.9 (m, 4H), 7.2-7.45 (m, 8H), 7.63 (fine d, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:19])=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7]=2[CH:18]=1.[O:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.[BH3-]C#N.[Na+]>CO>[Cl:2][C:3]1[C:4]([F:19])=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:13][CH2:14][N:15]([CH:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)[CH2:16][CH2:17]3)[C:7]=2[CH:18]=1
Reactant: O=C1CCOCC1
Reactant: O=c1[nH]c2cc(F)c(Cl)cc2n1C1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c2cc(F)c(Cl)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-Chloro-5-fluoro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D5) (0.286 mmol, 77 mg), Ti(iPrO)4 (2 eq., 0.572 mmol, 0.170 ml), tetrahydro-4H-pyran-4-one (2 eq., 0.572 mmol, 0.053 ml) were stirred together at room temperature for one hour; dry methanol (2 ml) followed by NaBH3CN (2 eq., 0.572 mmol, 36 mgs) were added and the mixture was stirred under argon at room temperature for 3 hours. The crude mixture was subsequently quenched with water (5 ml) and it was firstly purified by SCX followed by chromatography (methanol-NH3-dichloromethane) to yield 6-chloro-5-fluoro-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, 15 mg, 13%, M++H=353, which was converted into the hydrochloride salt using 1M HCl in diethyl ether.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:14][O:15][CH3:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)(C)(C)C.[ClH:18]>CCOC(C)=O.O1CCOCC1>[ClH:18].[CH3:16][O:15][CH2:14][C:8]1([NH2:7])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: COCC1(NC(=O)OC(C)(C)C)CCOCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCC1(N)CCOCC1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl[4-(methoxymethyl)tetrahydro-2H-pyran-4-yl]carbamate (0.45 g, 0.0018 mol) in EtOAc (0.2 mL) was added 4M of hydrogen chloride in 1,4-dioxane (3 mL) and stirred for 2 h. The volatiles were removed under reduced pressure to give the desired compound which was directly used in next step without further purification. LCMS: (M+H)=146.2.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:20]([CH3:33])=[C:21]([CH3:32])[C:22]3[O:26][C:25]([CH3:28])([CH3:27])[CH:24](O)[C:23]=3[C:30]=2[CH3:31])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[ClH:34]>C(OCC)(=O)C>[ClH:34].[ClH:34].[CH2:6]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:20]([CH3:33])=[C:21]([CH3:32])[C:22]3[O:26][C:25]([CH3:27])([CH3:28])[CH:24]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[C:23]=3[C:30]=2[CH3:31])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1c(C)c(N2CCN(Cc3ccccc3)CC2)c(C)c2c1OC(C)(C)C2O
Reactant: C1CCNC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C)c(N2CCN(Cc3ccccc3)CC2)c(C)c2c1OC(C)(C)C2N1CCCC1
Yield: 93 %

Procedure:
Using pyrrolidine and 5-(4-benzyl piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 42, the free base was obtained in the same manner as in Example 57. The free base was treated with a 4 N hydrochloric acid in ethyl acetate solution (10 ml) to obtain the title compound. Yield 93%. mp. 224–227° C. (decomposition) (ethyl acetate-ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[NH:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:17]([C:21](O)=[O:22])[CH:18]([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:21](=[O:22])[C@H:17]([NH:16][C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:18]([CH3:20])[CH3:19])[CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1(C)CNCCC1c1ccc(Cl)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4-chlorophenyl)-3,3-dimethylpiperidine, isomer A (1.1 g, 4.92 mmol), Boc-D-Val-OH (1.068 g, 4.92 mmol), HOBT (1.656 g, 10.82 mmol), and triethylamine (3.43 mL, 24.58 mmol) in methylene chloride (20 mL) was treated with EDC (2.073 g, 10.82 mmol), and the reaction was allowed to stir overnight at room temperature. The mixture was concentrated in-vacuo, and the residue was taken up in ethyl acetate. The organic phase was washed 3× with 1M NaOH, 3× with 1M HCl, and once with brine, dried over sodium sulfate, and concentrated in-vacuo to yield the title compound (2.25 g). MS (ESI+)=423.5, (M+H)+.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[C:7]([CH3:15])[C:5]=2[N:6]=1.N([O-])=O.[Na+].P(P(O)(O)=O)(O)(O)=O>P(=O)(O)(O)O.O>[CH3:15][C:7]1[C:5]2[N:6]=[CH:2][S:3][C:4]=2[CH:10]=[CH:9][C:8]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc2sc(N)nc2c1C
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: O=P(O)(O)P(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc2scnc2c1C
Temperature: -8 °C
Reaction time: 8 h

Procedure:
15 g of methyl 2-amino-4-methylbenzothiazole-5-carboxylate (0.07 mol) were initially charged in 450 ml of phosphoric acid, and the mixture was cooled to −8° C. 27.9 g of NaNO2 (0.4 mol) in 30 ml of water were then added dropwise such that the temperature did not exceed −4° C. The diazonium salt was then added dropwise, at 5-10° C., to 169 ml of hypophosphoric acid, and the mixture was stirred at 20° C. overnight. The reaction solution was then neutralized and extracted exhaustively with ethyl acetate. The organic phases Age were washed and dried and the solvent was then removed.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][C:23]2[CH:28]=[C:27]([Br:29])[C:26]([Cl:30])=[CH:25][C:24]=2[O:31][CH3:32])=[C:13](/[CH:15]=[CH:16]/[C:17](OCC)=[O:18])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([C:23]1[CH:28]=[C:27]([Br:29])[C:26]([Cl:30])=[CH:25][C:24]=1[O:31][CH3:32])[C:17](=[O:18])[CH:16]=[CH:15]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cc(Br)c(Cl)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)c(Br)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Temperature: 70 °C
Yield: 43.7 %

Procedure:
A RBF was charged with (E)-ethyl 3-(5-(benzylthio)-2-((5-bromo-4-chloro-2-methoxyphenyl)amino)phenyl)acrylate (6.80 g, 12.76 mmol) and MeOH (63.8 ml) to give a yellow suspension. Sodium methoxide, 25 wt % solution in methanol (10.21 ml, 5.10 mmol) was added, the RBF was fitted with a reflux condenser and the reaction was heated at 70° C. overnight. The reaction was cooled to RT and concentrated in vacuo. The crude material was concentrated onto silica gel and purified via MPLC, eluting with 50% ethyl acetate in heptanes (with 10% DCM additive) (isocratic). The impure material retrieved from column chromatography was dissolved in DCM and further purified via SCX column (product eluted with the methanol wash). The methanol filtrate was concentrated in vacuo and then the solids were triturated in IPA, filtered over a frit washing with minimal IPA to yield 6-(benzylthio)-1-(5-bromo-4-chloro-2-methoxyphenyl)quinolin-2(1H)-one (2.71 g, 5.57 mmol, 43.6% yield) as a beige solid. m/z (ESI) 486.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.Br[C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNC1CCCCC1NC>[Cu](I)I.C(OCC)(=O)C.C(O)(=O)C.O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Reactant: Cc1cc(C)nc(Br)c1
Agent: I[Cu]I
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(F)ccc2n1-c1cc(C)cc(C)n1
Temperature: 110 °C
Reaction time: 120 h
Yield: 84.8 %

Procedure:
4.35 g (21 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate, 4.29 g (23.1 mmol) of 2-bromo-4,6-dimethylpyridine, 9.36 g (44.1 mmol) of tripotassium phosphate, 0.66 ml (4.2 mmol) of 1,2-dimethylaminocyclohexane, 0.2 g (1.05 mmol) of copper iodide and 21 ml of dry toluene are added to a pressure tube. The tube is closed and the reaction mixture is stirred at 110° C. for 5 days. After this time, the mixture is poured onto a solution of 100 ml of water and the pH of the medium is adjusted to pH 5 by additions of acetic acid. 100 ml of ethyl acetate are added. The organic phase is separated, washed successively with 50 ml of water and 50 ml of a saturated aqueous sodium chloride solution, then dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue is purified by preparative chromatography (eluent: dichloromethane/ethyl acetate). 5.56 g of expected product are obtained, which product is used as is in the continuation of the synthesis.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH2:13][C:14]1[CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=1.C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:2]2[C:14]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]3)[CH2:13][NH:12][C:3]2=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(CNc2ccc(C(F)(F)F)cc2Br)C1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CNc3ccc(C(F)(F)F)cc32)C1
Reaction time: 15 h
Yield: 42.2 %

Procedure:
tert-Butyl 3-(((2-bromo-4-(trifluoromethyl)phenyl)amino)methyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (6.46 g, 15.3 mmol) was dissolved in benzene (300 mL). Thereafter, tributyltin hydride (6.02 mL, 23.0 mmol) and azobisisobutyronitrile (380 mg, 2.31 mmol) were added to the above obtained solution at room temperature, and the thus obtained mixture was then stirred for 15 hours while heating under reflux. Thereafter, the reaction solution was concentrated in vacuo, and the obtained residue was then purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain tert-butyl 5-(trifluoromethyl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (2.21 g, 42%) in the form of a colorless amorphous product.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.O1CCCC1.S(Cl)(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[Cl:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:46][C:45]1[CH:44]=[CH:43][C:26]([O:27][C:28]2[CH:29]=[CH:30][C:31]3[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]4[CH2:42][CH2:41]4)=[O:39])[N:36]=3)[CH:33]=2)=[CH:25][C:24]=1[NH:23][C:7]([C:5]1[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:8]
Reactant: Cn1cc(C(=O)O)c(C(F)(F)F)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cn1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2Cl)c(C(F)(F)F)n1
Yield: 37.5 %

Procedure:
In the same manner as in Example 55 and using 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (70.8 mg, 0.365 mmol), tetrahydrofuran (5 mL), thionyl chloride (63.3 μL, 0.730 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-chlorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (112 mg, 0.326 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (63.6 mg, 38%) was obtained as a white solid.
Reaction SMILES: CC(C)(OC([NH:7][CH2:8][C:9]([NH:11][CH:12]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])=O)C.Cl>O1CCOCC1>[NH2:7][CH2:8][C:9]([NH:11][CH:12]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10]
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)OC(C)(C)C)c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CC(NC(=O)CN)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 135.2 %

Procedure:
232 g (0.66 mole) of ethyl β-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxoethyl]amino]-pyridine-3-propanoate (from Step C) was dissolved in 1 liter of warm dioxane. After cooling to room temperature, 1.6 liters of 4M HCl in dioxane (Aldrich) was slowly added. A white precipitate formed after several minutes and then turned to a thick goo. After 2 hours, the solvent was decanted off. Ether was slurried and decanted several times until a white solid resulted. This was dried under vacuum to yield 224.2 g of ethyl β-[(2-amino-1-oxoethyl]amino]pyridine-3-propanoate, bis(hydrochloride) salt as a white hygroscopic solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[CH:9]2)([O-])=O.O.C(=O)([O-])[O-].[K+].[K+].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>O1CCCC1.Cl.[Cl-].[Ti+3].[Cl-].[Cl-]>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([S:14]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[CH:9]2
Reactant: O=[N+]([O-])c1cccc2cc(S(=O)(=O)c3ccccc3)cnc12
Agent: [Ti+3]
Agent: Cl
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc2cc(S(=O)(=O)c3ccccc3)cnc12
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
A slurry of 8-nitro-3-phenylsulfonylquinoline (D4) (46.7 g, 172 mmol), in tetrahydrofuran (750 ml) was added to a stirred solution of 30% titanium (III) chloride in aqueous HCl (470 ml) [Supplied by BDH] cooled in an ice bath, at such a rate that the temperature was maintained below 35° C. Once the addition was completed, the solution was stirred for a further 10 minutes then water (1.5 L) was introduced and the mixture poured into a 5 L beaker. The rapidly stirred solution was treated by portionwise addition of solid potassium carbonate in order to attain pH ˜8.5. EDTA (250 g, 0.86 mol) was added and followed by further potassium carbonate to maintain pH ˜8.5. The mixture was extracted with dichloromethane (3×1 L) and the combined organic phase passed through a silica plug (500 g) eluting with further dichloromethane (1 L) and 10% ethyl acetate in dichloromethane (1 L). The combined organic phases were evaporated and the residue subjected to purification using Biotage Flash-75 chromatography apparatus (2 kg silica gel), eluting with dichloromethane and increasing proportions of ether to give the title compound (D5) (34.5 g, 72%) as a pale brown solid;
Reaction SMILES: [C:1]1(=[O:10])[O:9][C:6]([CH3:8])([CH3:7])[O:5][C:3](=[O:4])[CH2:2]1.C(N(CC)CC)C.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1.Cl>CS(C)=O.O>[CH3:7][C:6]1([CH3:8])[O:9][C:1](=[O:10])[C:2]([C:27](=[O:28])[NH:26][C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:18])([F:30])[F:29])=[CH:21][CH:22]=2)=[C:3]([OH:4])[O:5]1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)OC(=O)C(C(=O)Nc2ccc(C(F)(F)F)cc2)=C(O)O1

Procedure:
To a solution of 14.4 g of isopropylidene malonate in 150 ml of dimethyl sulphoxide were added dropwise, at room temperature, 10.1 g of triethylamine and thereafter, at 20° to 30° C., 18.7 g of 4-trifluoromethylphenylisocyanate. The mixture was reacted for 12 to 15 hours at room temperature and the resultant solution was poured into a solution of 15 ml of concentrated hydrochloric acid in 350 ml of water. The precipitate which formed was collected with suction. Recrystallisation from 130 ml of acetone yielded the product of the formula ##STR5## with a melting point of 206°-208° C.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]4[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[C:16]([CH3:28])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[Cs+].[Cs+].[C:35](OCCBr)(=[O:37])[CH3:36].[OH-].[Na+]>CN(C)C=O.CO.O>[C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH:25]4[CH2:27][CH2:26]4)=[CH:23][CH:24]=3)=[C:16]([CH3:28])[N:15]([CH2:36][CH2:35][OH:37])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: Cc1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(C2CC2)cc1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1c(Cc2ccc(C3CC3)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1CCO
Reaction time: 2 h

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-5-methyl-4-[(4-cyclopropylphenyl)methyl]-1H-pyrazole (33 mg) and cesium carbonate (138 mg) in N,N-dimethylformamide (1 mL) was added 2-bromoethyl acetate (0.035 mL) at 40° C., and the mixture was stirred for 2 hours. To the reaction mixture was added water, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol). The obtained crude product was dissolved in methanol (1 mL), and to the solution was added 2 mol/L aqueous sodium hydroxide solution (0.04 mL), and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on ODS (developing solvent: methanol/water=3/2) to give 3-(β-D-glucopyranosyloxy)-1-(2-hydroxyethyl)-5-methyl-4-[(4-cyclopropylphenyl)methyl]-1H-pyrazole (8 mg).