Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C@:8]2([CH3:27])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9]2)[CH:7]=1.C(N(CC)C(C)C)(C)C.[Cl:38][C:39]1[CH:40]=[C:41]([CH3:48])[C:42]([C:45](O)=[O:46])=[N:43][CH:44]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:19]([NH:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:45](=[O:46])[C:42]3[C:41]([CH3:48])=[CH:40][C:39]([Cl:38])=[CH:44][N:43]=3)[CH:3]=[CH:4][C:5]=2[F:28])([CH3:27])[N:9]=1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccccc2)=N1
Reactant: Cc1cc(Cl)cnc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1C(=O)Nc1ccc(F)c([C@]2(C)C[C@@H](C(F)(F)F)OC(NC(=O)c3ccccc3)=N2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.5 %

Procedure:
A round-bottomed flask was charged with N-((4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (rac-4l, 0.233 g, 0.589 mmol), DCM (8 mL), N,N-diisopropylethylamine (0.133 mL, 0.766 mmol), 5-chloro-3-methylpicolinic acid (intermediate 6) 0.131 g, 0.766 mmol) and finally with 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate; 0.347 mL, 0.589 mmol). The reaction mixture was stirred at room temperature for 15 min. The Reaction mixture was poured into aqueous saturated NaHCO3 (50 mL) and then extracted with EtOAc (2×50 mL). The combined extracts were washed with brine, dried over Na2SO4 and loaded onto silica gel. Purification by silica gel chromatography (gradient 0 to 30% EtOAc/hexane) gave the title compound (50 mg). MS m/z=549.1 [M+H]+. Calculated for C26H21ClF4N4O3: 548.9
Reaction SMILES: CC(C)([O-])C.[K+].[SH:7][CH:8](O)[CH3:9].Br[CH2:12][CH2:13][C:14]1[C:15]2[N:16]([N:27]=[CH:28][N:29]=2)[C:17]([NH2:26])=[N:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)(C)(C)C>[CH2:8]([S:7][CH2:12][CH2:13][C:14]1[C:15]2[N:16]([N:27]=[CH:28][N:29]=2)[C:17]([NH2:26])=[N:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:9]
Reactant: Nc1nc(-c2ccccc2)c(CCBr)c2ncnn12
Reactant: CC(O)S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCSCCc1c(-c2ccccc2)nc(N)n2ncnc12
Temperature: 25 °C
Yield: 18.3 %

Procedure:
To a solution of 1.08 g (9.7 mmole) of potassium t-butoxide in 30 ml of cold (circa 0°) t-butyl alcohol was added 0.8 g (12.9 mmole) of mercaptoethanol, and the mixture was allowed to warm to room temperature. The title compound of Example 19 (2.05 g, 6.4 mmole) was added and the mixture was heated at reflux for two hours. Upon cooling, the mixture was concentrated in vacuo and the residue was treated with 50 ml of water. The mixture was extracted with chloroform/dichloromethane and the organic phase was washed with water, dried over magnesium sulfate, filtered, and concentrated to dryness. Column chromatography of the crude product on silica gel afforded 350 mg of the title compound, m.p. 120°-122°.
Reaction SMILES: [CH2:1]([C:8](Cl)=[S:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:11]1[CH:15]=[C:14]([C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)[N:13]=[CH:12]1>N1C=CC=CC=1>[CH2:1]([C:8]([N:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=[C:16]1[C:14]1[N:13]=[CH:12][S:11][CH:15]=1)=[S:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2[nH]c(-c3cscn3)nc2c1
Reactant: S=C(Cl)Cc1ccccc1
Solvent: c1ccncc1
Product: S=C(Cc1ccccc1)n1c(-c2cscn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
17.0 G. (0.091 moles) of benzylthiocarbonyl chloride is added dropwise under anhydrous conditions over a period of 25 minutes to a stirred suspension of 18.3 g. (0.091 moles) of 2-(4-thiazolyl)-benzimidazole in 140 ml. of pyridine. All of the solid material dissolved before the completion of the addition. When the addition is complete, precipitation of pyridine hydrochloride commences. The reaction mixture is stirred at room temperature for 18 hours, filtered and the pyridine solution evaporated to dryness in vacuo. The residue is dissolved in 250 ml. of methylene chloride filtered and the filtrate washed twice with 250 ml. of 0.25 normal hydrochloric acid and 200 ml. of saturated sodium bicarbonate solution. The methylene chloride is dried, treated with charcoal, filtered and evaporated to dryness in vacuo affording a solid material which is recrystallized from toluene affording 14.3 g. (45%) of 1-benzylthiocarbonyl-2-(4-thiazolyl)-benzimidazole, melting point 122° to 123° C.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[C:8]([C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH:15]=O)([CH3:11])([CH3:10])[CH3:9].N1CCCCC1>C(O)C>[C:21]([C:18]1[CH:17]=[C:14]([CH:15]=[C:5]2[S:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])[CH:13]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:19]=1[OH:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)c1cc(C=C2SC(=O)NC2=O)cc(C(C)(C)C)c1O
Yield: 42.7 %

Procedure:
To a solution of 12.5 g (107 mmol) of 2,4-thiazolidinedione and 25.0 g (107 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde in 300 ml of ethanol, 1.05 ml (10.7 mmol) of piperidine was added, and the mixture was heated under reflux for 5 hours. After cooling, the precipitated crystals were filtered and washed with cooled ethanol to give 15.23 g of the desired compound (42.8% yield, pale yellow crystals).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:28]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36][SH:37])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29].C(OCC)(=O)C>CN(C=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[C:8]([S:37][CH2:36][C:35]2[CH:38]=[CH:39][C:32]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:33][CH:34]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(Cl)c(CO[Si](C)(C)C(C)(C)C)c1=O
Reactant: CC(C)(C)c1ccc(CS)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 2-tert-butyl-4-tert-butyldimethylsilyloxymethyl-5-chloro 3(2H)-pyridazinone (1.5 g, 4.54 mmol) in DMF (10 ml) is added anhydrous cesium carbonate (2.9 g, 9.09 mmol) and 4-tert-butybenzyl mercaptan (1.02 g, 4.54 mmol). The mixture is stirred for 2 hours at 70° C. and then cooled to room temperature and ethyl acetate is added to it. The solution is then washed with water, dried and concentrated and the residue subjected to purification by flash chromatography (silica gel; ethyl acetate/hexanes) to give the above compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15](Br)[CH:16]=[C:11]2[C:10]([C:18](=[O:28])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:20]=2[F:27])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:30]3[S:29][CH:33]=[CH:32][CH:31]=3)[CH:16]=[C:11]2[C:10]([C:18](=[O:28])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:20]=2[F:27])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(Br)cc23)c1F
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(-c4cccs4)cc23)c1F
Yield: 85 %

Procedure:
To 5-bromo-3-(2-fluoro-3-methoxy-benzoyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (86, 350.0 mg, 0.78 mmol) in tetrahydrofuran (30 mL) and water (10 mL) were added 2-thiophene boronic acid (190 mg, 1.49 mmol), tetrakis(triphenyl-phosphine)palladium(0) (40.0 mg, 0.0346 mmol) and potassium carbonate (780 mg, 5.64 mmol) under an atmosphere of nitrogen. The reaction mixture was refluxed for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give crude compound (87, 0.30 g, 85%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CN(C=O)C.[CH3:10][C:11]1[C:16]2[NH:17][C:18](=[O:20])[O:19][C:15]=2[CH:14]=[CH:13][CH:12]=1.[CH3:21][C:22](OC(C)=O)=[O:23]>O>[C:22]([C:13]1[CH:12]=[C:11]([CH3:10])[C:16]2[NH:17][C:18](=[O:20])[O:19][C:15]=2[CH:14]=1)(=[O:23])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc2oc(=O)[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C)c2[nH]c(=O)oc2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
20.0 g (149.99 mmol) aluminium(III) chloride were combined with 5.0 mL DMF, with cooling. After 15 min stirring, first of all 5.0 g (33.52 mmol) 4-methylbenzo[d]oxazol-2(3H)-one and then 5.0 mL (52.90 mmol) acetanhydride were added and the mixture was stirred for 1 h at 80° C. The cooled reaction mixture was mixed with water. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [Na].CCO.[C:5]([NH:8][CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH3:6].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([CH2:30][CH3:31])[CH:23]=1>O1CCOCC1>[C:5]([NH:8][C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([CH2:30][CH3:31])[CH:23]=1)([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH3:6]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCc1ccc(CBr)cc1CC
Agent: [Na]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(CC)c(CC)c1)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere 8.14 g (354 mmol) of sodium was added in batches to 200 mL abs. EtOH and stirred until fully dissolved. 76.9 g (354 mmol) diethyl 2-acetylaminomalonate was then added to this solution, whereupon the sodium salt formed was precipitated. After the addition of 150 mL 1,4-dioxane a solution of 80 g (352 mmol) of 4-bromomethyl-1,2-diethyl-benzene in 500 mL of 1,4-dioxane was added dropwise to this suspension. The reaction solution was kept at 50° C. for 2 hours and then stirred for 16 hours at RT. The solvent was distilled off i. vac., the oily residue was combined with water, while the product was obtained in the form of white crystals. These were suction filtered, washed with water and reacted without any further purification.
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]4[O:17][CH:18]([CH2:20][OH:21])[CH2:19][C:9]=4[C:8]=3[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CC(C)=[O:24].S(=O)(=O)(O)O>[O-2].[O-2].[O-2].[Cr+6].O>[F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]4[O:17][CH:18]([C:20]([OH:24])=[O:21])[CH2:19][C:9]=4[C:8]=3[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2ccc3c(c2oc2cccc(F)c12)CC(CO)O3
Reactant: CC(C)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: O=C(O)C1Cc2c(ccc3c(=O)c4c(F)cccc4oc23)O1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled mixture of 8.0 g of the 7-fluoro-1,2-dihydro-2-hydroxymethyl-6-oxo-6H-furo[2,3-c]xanthene obtained in Example 27 and 1,000 ml of acetone, a mixture of chromium trioxide (14 g), water (80 ml) and concentrated sulfuric acid (24 g) was added dropwise under agitation. The resulting mixture was left to stand overnight and filtered. The filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from N,N-dimethylformamide (DMF) gave 8.1 g of 7-fluoro-1,2-dihydro-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p. 262°-265° C. This compound produced a mass spectrum having a molecular ion peak at m/e 300.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C:8]([C:10]1[CH:15]=[N:14][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][N:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O>[Br-].[Li+].CC(=O)CC>[C:1]([O:5][C:6](=[O:23])[CH:7]([Br:24])[C:8]([C:10]1[CH:15]=[N:14][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][N:11]=1)=[O:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cnc(NC(=O)C(C)(C)C)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: [Br-]
Agent: [Li+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)C(Br)C(=O)c1cnc(NC(=O)C(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1-L round bottomed flask equipped with a magnetic stirrer was charged with 73.00 mg (0.841 mmol) of lithium bromide and the butanone solution obtained in step 3 (ca. 100 mL), which theoretically contained 27.09 g (84.30 mmol) of 3-[5-(2,2-dimethyl-propionylamino)-pyrazin-2-yl]-3-oxo-propionic acid-tert-butyl ester and ca. 73 mL of butanone. To the resulting mixture was added a total of 15.16 g (85.17 mmol) of N-bromosuccinimide portionwise with careful reaction monitoring by HPLC. After stirring at room temperature for 1 h, HPLC analysis indicated complete reaction. The reaction mixture was concentrated at 25° C./25 mmHg to a volume of ca. 70 mL, then diluted with 130 mL of ethyl acetate and washed with 3×100 mL L of water. After concentration at 35° C./60 mmHg to a volume of ca. 90 mL, the resulting suspension was diluted with 200 mL of heptane, and re-concentrated to a volume of ca. 90 mL. Then, 200 mL of heptane was added, and the suspension was again concentrated to a volume of ca, 150 mL. The solid was then collected by filtration, washed with 2×50 mL of heptane and dried by suction to give 32.16 g of the title compound as a light yellow solid; 98.7% pure as determined by HPLC analysis (HPLC column Zorbax XDB-C8, 3×100 mm, 3.5 μm, eluent 20-100% acetonitrile/water+01. % TFA over 10 min at 0.5 mL/min, detection at UV 254 nm, retention time 9.52 min).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH2:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[C:24]1=[O:31])[CH3:16].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:28]([CH:25]1[CH2:26][CH2:27][N:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:15][CH3:16])[C:24]1=[O:31])=[O:29]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CCc1ccccc1N1CCC(C(=O)O)C1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1ccccc1N1CCC(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)C1=O
Yield: 53 %

Procedure:
This compound was prepared according to method E with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), 1-(2-ethylphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.101 g; 0.433 mmol), PyBOP (0.225 g; 0.433 mmol), N,N diisopropylethylamine (0.186 mL; 1.08 mmol) in DMF (3 mL). The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.094 g (53%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(2-ethylphenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:20]([F:23])([F:22])[F:21])=[C:9]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:24]([OH:26])=O.CN(C)C=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49][NH2:50])=[CH:47][CH:46]=1>O>[Cl:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49][NH:50][C:24]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([C:20]([F:21])([F:22])[F:23])[CH:7]=3)=[O:26])=[CH:47][CH:46]=1
Reactant: O=C(O)c1cnc2cc(C(F)(F)F)c(SCc3ccccc3)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(C(F)(F)F)c(SCc3ccccc3)cc2c1O
Temperature: 37.5 °C
Reaction time: 20 h

Procedure:
A mixture of 0.15 g of 4-hydroxy-6-[(phenylmethyl)thio]-7-(trifluoromethyl)-3-quinolinecarboxylic acid and 1.2 mL of dimethylformamide is treated with 0.075 g of carbonyldiimidazole. The mixture is stirred 20 h at 35-40° C. The solution is cooled to 25° C. and it is treated with 0.075 mL of distilled water and then it is stirred for 10 min. The solution is treated with 0.053 mL of 4-chlorobenzylamine and it is stirred for 18 h. The mixture is diluted with 1.0 mL of distilled water and then it is decanted from a dark, oily precipitate. This precipitate is treated with 1 mL of glacial acetic acid and the mixture is shaken for 5 min. The solid which formed is collected by filtration and it is washed with a few mL of 50% aqueous acetic acid. The solid is dried in a stream of air to give 48 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]2[OH:29])=[CH:12][CH:11]=1.Cl[CH2:34][C:35]1[CH:36]=[CH:37][C:38]2[O:43][CH2:42][C:41](=[O:44])[N:40]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:39]=2[CH:50]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH:17]2[O:29][CH2:34][C:35]2[CH:36]=[CH:37][C:38]3[O:43][CH2:42][C:41](=[O:44])[N:40]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:39]=3[CH:50]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cccc(F)c3)cc2)C(O)C1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4cccc(F)c4)cc3)cc21

Procedure:
Analogously to Method D, 1.1 g of tert-butyl 4-{4-[3-(3-fluorophenoxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.687 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as an opaque oil. Rf=0.42 (1:1 EtOAc-heptane); Rt=5.97.
Reaction SMILES: [Cl-].[C:2]1([N+:8]2[C:13]([Cl:14])=[C:12]([Cl:15])[C:11]([NH2:16])=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O>[Cl-:14].[C:2]1([N+:8]2[C:13]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:12]([Cl:15])[C:11]([NH2:16])=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Nc1cn[n+](-c2ccccc2)c(Cl)c1Cl
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: Nc1cn[n+](-c2ccccc2)c(Nc2ccccc2)c1Cl
Temperature: 10 °C
Yield: 84.6 %

Procedure:
30 parts of 1-phenyl-4-amino-5,6-dichloropyridazinium chloride in 150 parts of water is stirred with 18 parts of aniline for 10 minutes at 50°C. The solution has 50 parts of concentrated hydrochloric acid added to it and is cooled to 10°C. 30.5 parts (84.6% of theory) of 1-phenyl-4-amino-5-chloro-6-anilinopyridazinium chloride is obtained; C16H14N4Cl2, melting point (with decomposition) 130°C after having been recrystallized from water.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)([OH:13])[CH2:9]1)C1C=CC=CC=1.C([SiH](CC)CC)C>[Pd].CO>[F:21][C:16]1[CH:15]=[C:14]([C:10]2([OH:13])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: OC1(c2ccc(F)c(F)c2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CO
Product: OC1(c2ccc(F)c(F)c2)CCNC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
A mixture of enantiomer E1 of 1-benzyl-3-(3,4-difluorophenyl)pyrrolidin-3-ol (0.81 g, 2.8 mmol), methanol (15 mL) and palladium on carbon (160 mg) was purged with nitrogen. Triethyl silane (6.5 g, 56 mmol) was added drop wise and the resulting mixture was stirred at ambient temperature for 3 h after which the mixture was filtrated over celite and evaporated. Methanol (15 mL) and palladium on carbon (160 mg) was added and the mixture was purged with nitrogen. Triethyl silane (6.5 g, 56 mmol) was added in 5 equal portions over 1.5 h and the resulting mixture was stirred at ambient temperature for 11.5 h. The mixture was filtrated over celite, evaporated and purified on a Biotage (solute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) to give the title compound (0.52 g). MS m/z (relative intensity, 70 eV) 199 (M+, bp), 141, (97), 127 (54), 114 (48), 113 (85).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([C:15]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[O:16])[CH:14]=1)[C:7]([O:9]CC)=[O:8])#[N:2].O.[OH-].[Li+].Cl>C(O)C.O>[C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([C:15]([N:17]([CH2:18][CH2:19][CH3:20])[CH2:21][CH2:22][CH3:23])=[O:16])[CH:14]=1)[C:7]([OH:9])=[O:8])#[N:2]
Reactant: CCCN(CCC)C(=O)c1cc(CC#N)cc(C(=O)OCC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCN(CCC)C(=O)c1cc(CC#N)cc(C(=O)O)c1

Procedure:
A mixture of ethyl 3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoate (1.5 g) and phosphorous tribromide (0.95 mL) is stirred in dichloromethane (10 mL) and heated at 50 degrees C. for 4 hours and then cooled and partitioned between dichloromethane and water. The organic phase is separated and washed with aqueous sodium bicarbonate and then dried over magnesium sulfate and taken to dryness to give ethyl 3-(bromomethyl)-5-[(dipropylamino)carbonyl]benzoate, high resolution MS MH+=370.1020. Ethyl 3-(bromomethyl)-5-[(dipropylamino)carbonyl]benzoate (1.4 g) and sodium cyanide (0.2 g) are stirred in dry DMSO (25 mL) at 20-25 degrees C. for 3.5 hours and the mixture is then partitioned between ethyl acetate, water and saline. The organic layer is separated and dried over magnesium sulfate and taken to dryness under reduced pressure to give ethyl 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoate. Ethyl 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoate (0.6 g) is hydrolyzed with lithium hydroxide monohydrate (0.1 g) in ethanol and water at 20-25 degrees C. overnight and then added to water (50 mL). The pH is adjusted to 4 using concentrated hydrochloric acid and the mixture is partitioned between ethyl acetate, water, and saline. The organic phase is separated and dried over magnesium sulfate and taken to dryness under reduced pressure to give 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoic acid, MS M+H=287.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[NH:9][C:5]=2[CH:4]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH:30][CH:31]([CH2:36][CH:37]3[O:39][CH2:38]3)[C:32]([O:34]C)=[O:33])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([NH:30][CH:31]([CH2:36][CH:37]([OH:39])[CH2:38][S:10][C:8]3[NH:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=4[N:7]=3)[C:32]([OH:34])=[O:33])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nc4ccc(OC)cc4[nH]3)C(=O)O)cc2)cc1

Procedure:
Example 41 is prepared from 5-methoxy-2-benzimidazolethiol and 1d using the procedure described for compound 20.