Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13](O)=[O:14])[CH:5]=[CH:6][CH:7]=1.[NH2:29][C:30]1[S:31][CH:32]=[CH:33][N:34]=1>>[S:31]1[CH:32]=[CH:33][N:34]=[C:30]1[NH:29][C:13]([C:12]1[S:11][C:10]([N:16]2[C:20]3[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=3[N:18]=[CH:17]2)=[N:9][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:14]
Reactant: Nc1nccs1
Reactant: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)O)s3)c2cc1OC
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)Nc4nccs4)s3)c2cc1OC
Yield: 79.5 %

Procedure:
In a similar manner as described for Example 53, 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (41 mg, 0.1 mmol) and 2-aminothiazole (10.0 mg, 0.1 mmol, Aldrich) gave 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid thiazol-2-ylamide (39.6 mg, 79.5%) as a white solid. MS m/z 498 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](I)[CH:4]=[C:3]1[C:8]([O:10][CH3:11])=[O:9].[CH3:12][C:13]1([CH3:32])[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[C:23]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][C:19](B(O)O)=[CH:20]3)=[CH:15][C:14]1=2.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([C:19]2[CH:18]=[CH:17][C:16]3[C:21](=[CH:22][C:23]4[C:24]([CH3:28])([CH3:27])[CH2:25][CH2:26][C:13]([CH3:32])([CH3:12])[C:14]=4[CH:15]=3)[CH:20]=2)[CH:4]=[C:3]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(I)cn1C
Reactant: CC1(C)CCC(C)(C)c2cc3cc(B(O)O)ccc3cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccc3cc4c(cc3c2)C(C)(C)CCC4(C)C)cn1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.9 %

Procedure:
231 mg (0.2 mml) of tetrakis-(triphenylphosphine)palladium (0), 50 ml of toluene and 1.75 g (6.6 mmol) of methyl N-methyl-4-iodo-2-pyrrolecarboxylate were introduced into a three-necked flask and under a nitrogen stream and the mixture was stirred at room temperature for 20 minutes. 2.8 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthrylboronic acid and 6.6 ml of an aqueous potassium carbonate solution (2N) were then added and the mixture was heated at reflux for 8 hours. The reaction medium was evaporated to dryness, taken up in water and ethyl ether, the organic phase decanted, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (80/20). 840 mg (47%) of methyl N-methyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthryl)-2-pyrrolecarboxylate were obtained.
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[O:12][CH3:13].C([Li])(C)(C)C.[CH2:19]([O:26][CH2:27][C@H:28]1[CH2:37][CH2:36][C@:30]2([O:34][CH2:33][C:32](=[O:35])[CH2:31]2)[C@@H:29]1[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([O:26][CH2:27][C@H:28]1[CH2:37][CH2:36][C@:30]2([O:34][CH2:33][C@@:32]([OH:35])([C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=3[O:12][CH3:13])[CH2:31]2)[C@@H:29]1[C:38]1[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CO[C@]2(CC[C@H](COCc3ccccc3)[C@H]2c2ccc(F)cc2)C1
Reactant: COc1ccc(C(F)(F)F)cc1Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(F)(F)F)cc1[C@]1(O)CO[C@]2(CC[C@H](COCc3ccccc3)[C@H]2c2ccc(F)cc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
2-Bromo-4-(trifluoromethyl)anisole (227 mg, 0.89 mmol), prepared according to the procedure of J. Alexander (Org. Prep. Proced. Int., 1986, 18, 213-215), was dissolved in 3.7 mL of THF and cooled in a -78° C. bath. A solution of t-butyllithium (1.0 mL, 1.7M in hexane, 1.7 mmol) was added over a period of 2 min. After 30 min., a solution of 200 mg (0.56 mmol) of (5R,6S,7S)-7-(benzyloxymethyl)-6-(4-fluorophenyl)-1-oxaspiro[4.4]nonane-3-one (prepared from methyl (5R,6S,7S)-6-(4-fluorophenyl)-3-(methylene)-1-oxaspiro[4.4]nonane-7-carboxylate (from Example 9) by DIBALH reduction, benzylation with sodium hydride and benzyl bromide, and oxidation as described in Example 6, Step C) in 1.0 mL of THF was added, and the reaction was stirred for 45 min. at -78° C. followed by warming to -35° C. over 20 min. The reaction was quenched by the addition of 10 mL of saturated aqueous ammonium chloride and partioned between 30 mL of ethyl acetate and 10 mL of water. The organic layer was washed with 10 mL of saturated aqueous sodium bicarbonate and 10 mL of saturated aqueous sodium chloride, dried over sodium sulfate, decanted, and evaporated. The crude product was purified by flash column chromatography, eluting with 1.5-5% ethyl ether in toluene to give 154 mg of the title compound.
Reaction SMILES: [CH3:1][NH2:2].Cl.C[Al](C)C.C(O[C:11](=[O:31])[CH2:12][CH:13]([C:20]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][NH:24]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C>C1C=CC=CC=1>[CH3:30][O:29][C:28]1[C:20]([CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][C:11]([NH:2][CH3:1])=[O:31])=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[CH:22]2
Reactant: CN
Reactant: CCOC(=O)CC(c1ccccc1)c1c(OC)ccc2[nH]ccc12
Agent: C[Al](C)C
Agent: Cl
Solvent: c1ccccc1
Product: CNC(=O)CC(c1ccccc1)c1c(OC)ccc2[nH]ccc12
Temperature: 25 °C

Procedure:
To a 0° C. suspension of MeNH2.HCl (15.6 mg, 0.231 mmol) in benzene (2 ml) was added Me3Al (2M in toluene, 115 μl, 2.31 mmol). The mixture was stirred at 0° C. for 5 min and at RT for 2 hours after which a solution of 3-(5-methoxy-1H-Indol-4-yl)-3-phenyl-propionic acid ethyl ester XLIX in benzene (4 ml) was added. The reaction mixture was stirred at reflux for 5 hours and at room temperature for 16 hours, and quenched by addition of HCl (0.5 M). The aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated to yield crude 3-(5-Methoxy-1H-Indol-4-yl)-N-methyl-3-phenyl-propionamide L (37 mg, yellow oil), which was used without purification in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:3]=1.[CH3:28][S:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.COCCOC>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:4]2[CH:3]=[C:2]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([S:29][CH3:28])[CH:35]=3)[CH:7]=[CH:6][N:5]=2)[CH2:9][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[N:11]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(Br)ccn2)c(F)c1
Reactant: CSc1cccc(B(O)O)c1
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: CCO
Product: CSc1cccc(-c2ccnc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
5-(4-Bromo-pyridin-2-yl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (50.0 mg, 0.11 mmol) prepared in Step 4 of Preparation 11, 3-(methylthio)phenylboronic acid (28.0 mg, 0.17 mmol), Pd(PPh3)4 (12.8 mg, cat.) and a 2N sodium carbonate solution (550.0 uL) were added to a mixed solvent of ethanol (550.0 uL) and 1,2-dimethoxyethane (1.2 mL). The reaction mixture was stirred at 85° C. for 3 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 35.0 mg of the titled compound as a white liquid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10]([NH2:12])=[CH:9][CH:8]=[CH:7][C:6]=2[CH:5]=[N:4][CH:3]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[O:22])=[CH:17][CH:16]=1>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:21]([NH:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:26])[F:25])=[CH:24][CH:23]=2)=[O:22])[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncc2cccc(N)c12
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: Cc1cncc2cccc(NC(=O)NCc3ccc(C(F)(F)F)cc3)c12

Procedure:
Prepared fiom 4-methylisoquinolin-5-amine (Description 91) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 360 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:10][C:9]([C:6]1[NH:7][N:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:11]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])n[nH]1
Yield: 95 %

Procedure:
To a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (1.13 g, 7.19 mmol) in anhydrous methanol (20 ml) at to 0° C. was added thionyl chloride (2.23 g, 1.37 ml, 18.7 mmol) dropwise. The resulting solution was heated to reflux for 2 h. The cooled solution was evaporated to dryness to give 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (1.17 g, 95%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:30]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[C:25]=3[N:24]=[N:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:32]>CCO>[NH2:32][C:26]1[C:25]2[N:24]=[N:23][N:22]([C:16]3[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=3[NH:14][S:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=3)(=[O:12])=[O:13])[C:30]=2[CH:29]=[CH:28][N:27]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3c(Cl)nccc32)cc1
Reactant: N
Solvent: CCO
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3c(N)nccc32)cc1
Temperature: 120 °C

Procedure:
A 4 mL scintillation vial was charged with 4-tert-butyl-N-[4-chloro-2-(4-chloro-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-phenyl]-benzenesulfonamide (synthesized according to general procedure G, 20 mg, 0.042 mmol) and 2 M NH3 in EtOH (2 mL). The reaction was sealed and heated to 120° C. for 18 hours. The EtOH was then removed in vacuo and the resultant residue was purified by preparative TLC to afford N-[2-(4-amino-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-4-chloro-phenyl]-4-tert-butyl-benzenesulfonamide: MS (ES) M+H expected 457.1, found 457.0.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:14].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[CH2:20]([O:10][C:9]([CH:7]1[CH2:6][C:5]2[CH:12]=[CH:13][C:2]([Cl:1])=[C:3]([Cl:14])[C:4]=2[O:8]1)=[O:11])[CH3:21]
Reactant: O=C(O)C1Cc2ccc(Cl)c(Cl)c2O1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1Cc2ccc(Cl)c(Cl)c2O1

Procedure:
A solution of 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (70 g.) conc. sulfuric acid (2 ml.) and ethanol (250 ml.) is refluxed for 2 hours. The ethanol is distilled at reduced pressure and the residue is suspended in saturated sodium bicarbonate and extracted with ether. The ether solution is washed with brine, dried over magnesium sulfate and the ether distilled at reduced pressure. The 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid ethyl ester is used without further purification in the following synthesis.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[CH2:14]O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.S(Cl)([Cl:24])=O.C(O)=O>C1C=CC=CC=1>[C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[CH2:14][Cl:24])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CO)cc1OS(=O)(=O)c1ccc(C)cc1
Solvent: c1ccccc1
Solvent: O=CO
Product: COc1ccc(CCl)cc1OS(=O)(=O)c1ccc(C)cc1
Temperature: 17.5 °C
Yield: 90 %

Procedure:
To a cooled solution of 3-[(p-Toluenesulfonyl)oxy]-4-methoxybenzyl alcohol 22 (8.0 g, 26 mmol) in benzene (25 mL) was added thionyl chloride (1.9 mL, 26 mmol) slowly over a period of 5-10 min maintaining the temperature around 15-20° C. The reaction was maintained at those conditions for 2 h and checked TLC for the completion. The flask is connected to a high vacuum through a trap containing formic acid under mild heating to remove excess thionyl chloride. The slurry formed after complete removal of thionyl chloride and benzene, filtered, washed with hexane and dried to afford 23. Yield: 90%; white solid mp 102-105° C. 1H NMR: δ 2.43 (s, 3H, CH3), 3.61 (s, 3H, OCH3), 4.50 (s, 2H, CH2), 6.80-7.79 (m, 7H, Ar—H). Anal. Calcd for C15H15ClO4S: C, 55.13, H, 4.63. Found: C, 53.20, H, 4.59.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][C@@H:15]([N:37]=[N+:38]=[N-:39])[CH2:16][CH2:17][C@H:18]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[O:7][C@H:6]1[N:40]1[CH:48]=[N:47][C:46]2[C:41]1=[N:42][C:43]([NH:50][CH2:51][CH2:52][NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])=[N:44][C:45]=2[NH2:49])(=O)C.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CO>[NH2:49][C:45]1[N:44]=[C:43]([NH:50][CH2:51][CH2:52][NH:53][C:54]([O:56][C:57]([CH3:58])([CH3:59])[CH3:60])=[O:55])[N:42]=[C:41]2[C:46]=1[N:47]=[CH:48][N:40]2[C@@H:6]1[O:7][C@H:8]([CH2:14][C@@H:15]([N:37]=[N+:38]=[N-:39])[CH2:16][CH2:17][C@H:18]([NH:26][S:27]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)(=[O:29])=[O:28])[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C[C@H](CC[C@H](NS(=O)(=O)c2ccc(C)cc2)C(=O)OC(C)(C)C)N=[N+]=[N-])O[C@H]1n1cnc2c(N)nc(NCCNC(=O)OC(C)(C)C)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N[C@@H](CC[C@@H](C[C@H]2O[C@@H](n3cnc4c(N)nc(NCCNC(=O)OC(C)(C)C)nc43)[C@H](O)[C@@H]2O)N=[N+]=[N-])C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture consisting of Compound 28A in methanol is added potassium carbonate (10 molar equivalents) and the mixture stirred for 30 minutes at room temperature. Acetic acid is added to neutral pH and the solution is stirred 30 minutes. Solvent is evaporated and the mixture is partitioned between ethyl acetate and water. The organics are washed with brine, dried and evaporated. The residue is chromatographed on silica gel to obtain the title intermediate.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([O:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])=[CH:26][C:20]=4[S:19](=[O:37])(=[O:36])[N:18]=3)[C:7]2=[O:38])[CH2:3][CH2:2]1>FC(F)(F)C(O)=O.ClCCl>[CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:26][C:20]=4[S:19](=[O:37])(=[O:36])[N:18]=3)[C:7]2=[O:38])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)COc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
The product of Example 384A (195 mg, 0.36 mmol) in a mixture of trifluoroacetic acid (5 mL) and dichloromethane (5 mL) was stirred for three hours at 25° C. The solvents were removed under reduced pressure. The residue was triturated with hexanes/ethyl acetate (1:1) and filtered to give title compound (114 mg, 65%). 1H NMR (300 MHz, DMSO-d6) δ 0.14 (d, J=4.04 Hz, 2 H) 0.41 (d, J=7.35 Hz, 2 H) 1.02 (m, 1 H) 2.86 (d, J=6.25 Hz, 2 H) 4.88 (s, 2 H) 6.44 (s, 1 H) 7.39 (m, 3 H) 7.67 (d, J=8.82 Hz, 1 H) 7.89 (m, 1 H) 8.10 (d, J=8.46 Hz, 1 H) 8.17 (dd, J=1.47 Hz, J=6.62 Hz, 1 H) 13.16 (s, 1 H) 14.07 (s, 1 H) 15.12 (s, 1 H). MS (ESI−) m/z 483 (M−H)−.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:36])[C@@H:15]([O:33][CH2:34][CH3:35])[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][C:19]=1[Cl:32])[OH:17])C1C=CC=CC=1.[CH3:37][O-:38].[Na+]>CO>[CH3:37][O:38][C:14](=[O:36])[C@@H:15]([O:33][CH2:34][CH3:35])[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:20][C:19]=1[Cl:32])[OH:17]
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1Cl

Procedure:
In analogy to the procedure described in example 1 b], (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-chloro-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one was treated with sodium methoxide in methanol to give (2S,3R)-3-(4-benzyloxy-2-chloro-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester as colorless liquid. According to 1H-NMR spectroscopy, one single diastereomer was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1[NH:16][N:17]=[CH:18][C:13]=1[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][N:17]1[CH:18]=[C:13]2[CH2:12][CH2:11][C:10]3[C:15]([C:14]2=[N:16]1)=[C:2]([NH2:1])[C:3]1[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=1)[N:9]=3)[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: Nc1c2c(nc3ccccc13)CCc1cn[nH]c1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc2c(n1)-c1c(nc3ccccc3c1N)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 11-amino-4,5-dihydro-1H-pyrazolo[3,4-a]acridine (10 g) in dry DMF (300 ml) was added NaH (60%)(2.12 g) slowly. The reaction was stirred at room temperature for two hours, ethyl bromoacetate (6.0 ml) was added and the reaction was stirred for one hour.
Reaction SMILES: [F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15](C)=[CH:14][N:13](S(C3C=CC=CC=3)(=O)=O)[C:10]2=[N:11][CH:12]=1)=[O:5].[C:38]([O-])([O-])=O.[K+].[K+]>CO.O>[F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([CH3:38])[NH:13][C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(C)cn3S(=O)(=O)c2ccccc2)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(C)cc3c2)c1F

Procedure:
2,6-Difluoro-N-(3-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.654 g, 1.19 mmol) was dissolved in MeOH (9 mL) and water (3 mL). K2CO3 (3.295 g, 23.84 mmol) was added, and the reaction mixture was stirred at reflux overnight. The solution was partitioned between water and EtOAc. The organic layer was washed with water (3×), brine, dried over Na2SO4 and concentrated to a solid. The solid was triturated with DCM to provide 2,6-difluoro-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide as a solid (148 mg, 30% for three steps). 1H NMR (400 MHz, DMSO-d6) δ 11.31 (br s, 1H), 10.85 (s, 1H), 9.79 (br s, 1H), 8.31 (br s, 2H), 7.51-7.57 (m, 1H), 7.24-7.29 (m, 2H), 3.11-3.15 (m, 2H), 2.26 (br s, 3H), 1.75-1.80 (m, 2H), 0.98-1.02 (m, 3H); m/z (APCI-neg) M−1=407.2.
Reaction SMILES: ClC(OC(Cl)C)=[O:3].COC1C=CC(CN2CCN(CC3C=CC(N[C:29]([C:31]4[C:32]5[N:33]=[CH:34][CH:35]=[N:36][C:37]=5[C:38]([C:41]5[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[C:43]([O:49][CH3:50])[CH:42]=5)=[CH:39][CH:40]=4)=[O:30])=NC=3)CC2)=CC=1>C1COCC1>[CH3:48][O:47][C:45]1[CH:46]=[C:41]([C:38]2[C:37]3[N:36]=[CH:35][CH:34]=[N:33][C:32]=3[C:31]([C:29]([OH:30])=[O:3])=[CH:40][CH:39]=2)[CH:42]=[C:43]([O:49][CH3:50])[CH:44]=1
Reactant: COc1ccc(CN2CCN(Cc3ccc(NC(=O)c4ccc(-c5cc(OC)cc(OC)c5)c5nccnc45)nc3)CC2)cc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-c2ccc(C(=O)O)c3nccnc23)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
α-Chloroethyl chloroformate (19 μL, 0.17 mmol) was added to a cold (−78° C.) solution of 8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid {5-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]pyridin-2-yl}-amide (Example 116) (103 mg, 0.17 mmol) in THF (2 mL). The reaction mixture was stirred for 1 h at −78° C., quenched by addition of MeOH and concentrated. The residue was dissolved in MeOH (5 mL), heated to reflux for 3 h, allowed to cool. The resulting solid was collected by filtration, diluted in in DCM and a saturated aqueous solution of NaHCO3, and extracted with DCM. The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 91.5:7.5:1) followed by trituration in Et2O to afford 28 mg of the title compound as a white solid. Title compound: ESI-MS: 485.2 [M+H]+; tR=3.80 min (System 1); TLC: Rf=0.10 (DCM/MeOH/NH3aq, 91.5:7.5:1).
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:53]([O:55]CC)=[O:54])[C:7](=[O:52])[N:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[N:29]=[N:30][N:31]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:32]=2)=[CH:18][CH:17]=1)[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:53]([OH:55])=[O:54])[C:7](=[O:52])[N:8]2[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[N:29]=[N:30][N:31]([C:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:32]=2)=[CH:20][CH:21]=1)[CH3:2]
Reactant: CCOC(=O)c1cc2c(CC)nc(CC)cc2n(Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCc1cc2c(cc(C(=O)O)c(=O)n2Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CC)n1
Reaction time: 16 h
Yield: 46.6 %

Procedure:
Ethyl 5,7-diethyl-2-oxo-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2-dihydro-1,6-naphthyridine-3-carboxylate (0.41 g) was dissolved in dioxan (5 ml) containing aqueous 1M sodium hydroxide solution (0.55 ml) and the mixture was stirred for 16 hours. Volatile material was removed by evaporation and the residue was partitioned between ethyl acetate and water. The aqueous phase was separated, acidified to pH 4-5 with 1M aqueous citric acid solution and then extracted twice with dichloromethane. The combined extracts were dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by flash chromatography, eluting initially with ethyl acetate/petroleum ether (2:1 v/v), followed by ethyl acetate and then methanol/ethyl acetate (1:9 v/v), to give 5,7-diethyl-2-oxo-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2-dihydro-1,6-naphthyridine-3-carboxylic acid (A) (0.184 g) as a solid; NMR (d6 -DMSO+d4 -acetic acid): 1.15(t,3H), 1.32(t,3H), 2.68(q,2H), 3.22(q,2H), 5.66(s,2H), 6.8-7.9(complex m,24H), 9.06(s,1H); mass spectrum(+ve FAB, DMSO/NBA): 745(M+Na)+ ; microanalysis, found: C, 66.9; H, 5.0; N, 10.0%; C46H38N6O3.1.7SiO2 requires: C, 67.0; H, 4.6; N, 10.2%.