Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1(C(OCC)=O)[CH2:9][CH:8]2[CH2:10][CH2:11][CH2:12][CH:13]=[C:7]2[S:6]1)(=O)C.[C:19]([O:29][CH2:30][CH3:31])(=[O:28])C=CC1C=CC=CC=1.N1CCCC1>[Pd].C1(C)C=C(C)C=C(C)C=1>[NH2:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[C:9]=1[C:19]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C=Cc1ccccc1
Reactant: CCOC(=O)C1(NC(C)=O)CC2CCCC=C2S1
Agent: [Pd]
Solvent: Cc1cc(C)cc(C)c1
Solvent: C1CCNC1
Product: CCOC(=O)c1c(N)sc2ccccc12
Reaction time: 21 h
Yield: 64 %

Procedure:
2 g of palladium catalyst (5% Pd/C, approx. 50% moisture content; Degussa-Hüls; E 101 RW 5%) are added to a solution of 10 g of ethyl 2-acetylaminotetrahydrobenzothiophenecarboxylate in 80 ml of mesitylene and the mixture is heated to 170° under nitrogen. 2 g of ethyl cinnamate are metered in over 30 min and stirring is continued for 21 h. The temperature is then lowered to 100° and 10 ml of pyrrolidine are added. The reaction mixture is stirred for 25 h under nitrogen. The catalyst is then filtered off and rinsed with 60 g of ethanol. The solutions are combined and the solvent is distilled off. The residue is taken up in ethyl acetate and washed twice with 1 N HCl and once with water. After distillation of the solvent and subsequent crystallization from 2-propanol, ethyl 2-aminobenzo[b]thiophene-3-carboxylate is obtained with a yield of 64%.
Reaction SMILES: O=[C:2]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[CH:20]([O-:22])=O.[NH4+:23]>O>[CH:20]([NH:23][CH:2]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:22]
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(CC(=O)c2cccnc2)cc1
Reactant: O=C[O-]
Solvent: O
Product: COC(=O)c1ccc(CC(NC=O)c2cccnc2)cc1
Yield: 36.4 %

Procedure:
To 2.00 g of methyl 4-[2-oxo-2-(3-pyridyl)ethyl]benzoate was added 14.8 g of ammonium formate, for reaction at 150° C. for four hours, and followed by addition of water after cooling and extraction with chloroform. The organic phase was washed in saturated aqueous sodium chloride solution, dried over magnesium sulfate, followed by distillation of the solvent, to produce the residue. The residue was subjected to chromatography on a silica gel column, which was then eluted with chloroform-methanol (25:1 ) to produce 0.81 g of methyl 4-[2-formamido-2-(3-pyridyl)ethyl]benzoate.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[O:30][N:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[O:30][N:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[C:14]([C:17]([NH2:18])=[O:37])=[N:15][CH:16]=1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (74 mg, 0.257 mmol), 4-(isoxazol-5-yl)aniline (60 mg, 0.375 mmol), K2CO3 (80 mg, 0.579 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-(isoxazol-5-yl)phenylamino)pyrazine-2-carbonitrile (4 mg). The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-(isoxazol-5-yl)phenylamino)pyrazine-2-carbonitrile (4 mg, 0.010 mmol) was dissolved in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.50 mL) and aq. H2O2 (30%, 0.50 mL) were added. The mixture was stirred at room temperature for 60 min. HOAc (0.25 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (3 mg). MS 430.4 (M+H); UV 202.3, 234.0, 274.4, 331.8 nm; t 0.483 min.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]1.[O:19]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH2:9][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]2)[C:2]=1[C:29]1[CH:30]=[CH:31][C:26]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:27][CH:28]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1ncnc(Cl)c1Cl
Reactant: NCC1CCNC(=O)C1
Product: Nc1ncnc(NCC2CCNC(=O)C2)c1-c1ccc(Oc2ccccc2)cc1

Procedure:
4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-2-one was prepared from 5,6-dichloropyrimidin-4-amine, 4-(aminomethyl)piperidin-2-one, (4-phenoxyphenyl)boronic acid using methods I, and C. HPLC purity: 100%. MS: m/z=390 [M+H]+.
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:10]3[CH2:35][S:34](=[O:37])(=[O:36])[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:11]=3[N:12]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[N:13]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([C:7]([C:9]2[C:10]3[CH2:35][S:34](=[O:37])(=[O:36])[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:11]=3[N:12]([CH2:14][CH:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)[N:13]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1nn(CC2CCNCC2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-{[3-(morpholin-4-ylcarbonyl)-5,5-dioxidothiochromeno[4,3-c]pyrazol-1(4H)-yl]methyl}piperidine-1-carboxylate (0.1 g, 0.21 mmol) in DCM (2.0 mL) is added TFA (0.119 g, 1.05 mmol, 5 Eq) and the reaction mixture is stirred at room temperature overnight. The crude reaction mixture is washed with sodium bicarbonate then brine and dried over MgSO4. The crude residue is purified by flash chromatography to afford the title compound as a pale brown solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.03-7.98 (m, 2H), 7.88 (t, J=7.5 Hz, 1H), 7.73-7.70 (m, 1H), 4.78 (s, 2H), 4.47 (t, J=7.1 Hz, 2H), 3.91 (s, 2H), 3.66-3.63 (m, 6H), 2.98-2.95 (m, 2H), 2.00 (brs, 1H), 1.75-1.69 (m, 1H), 1.48-1.40 (m, 2H), 1.24-1.17 (m, 3H). MS (ESI+): 431.0. HPLC (max plot) 97.2%; Rt 2.16 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9](=O)[N:8]=[C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[F:20])[NH:6][C:5]=2[N:21]=1.P(Cl)(Cl)([Cl:24])=O.CN(C)C1C=CC=CC=1>CO.ClCCl>[Cl:24][C:9]1[C:4]2[S:3][C:2]([NH2:1])=[N:21][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc2[nH]c(SCc3cccc(F)c3F)nc(=O)c2s1
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Reaction time: 2 h

Procedure:
The product from example 1, step (a) (0.89 g), phosphorus oxychloride (12 ml) and N,N-dimethylaniline (1.2 ml) were heated at reflux for 2 hours. The cooled reaction mixture was poured onto ice water and stirred for 2 hours. Chromatography (SiO2, methanol/dichloromethane as eluant) gave the subtitled compound.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:13][C:14]1[C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=[C:16]2[S:23][C:24]([I:26])=[CH:25][C:15]=12.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.CC(O)=O>CN(C=O)C>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:20]([C:19]2[C:14]([OH:13])=[C:15]3[CH:25]=[C:24]([I:26])[S:23][C:16]3=[N:17][CH:18]=2)=[O:22])=[CH:30][CH:29]=1
Reactant: O=C(O)c1cnc2sc(I)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(I)cc2c1O
Temperature: 60 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
Mercuric oxide (7.10 g) and iodine (8.32 g) are added portion-wise to a solution of ethyl 4-hydroxythieno[2,3-b]pyridine-5-carboxylate (J. Heterocyclic Chem. 1977, 14, 807) (5.22 g) in CHCl3 (90 mL). The reaction is stirred at rt for 18 h. The reaction mixture is filtered, and the solid is washed with CHCl3 (400 mL). The organic layer is washed with H2O (200 mL), dried with MgSO4, filtered, and concentrated in vacuo. The resulting orange solid is purified by column chromatography (CH2Cl2:heptane, 1:1). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield 2.95 g (36%) of ethyl 4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxylate as a pale yellow solid. Ethyl 4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxylate (2.64 g) is suspended in 10% NaOH (21 mL) and heated to reflux. The reaction is stirred at reflux for 1 h and then cooled to rt. The reaction mixture is poured into H2O (80 mL). Conc. HCl is added until a precipitate forms, and 2.272 g (94%) of 4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxylic acid is isolated as a white solid. Carbonyldiimidazole (1.34 g) is added to a solution of 4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxylic acid (2.041 g) in DMF (58 mL). The reaction is heated to 60° C. and stirred for 18 h. The reaction mixture is cooled to rt, and 4-chlorobenzylamine (1.01 mL, 8.27) is added. The reaction is stirred at rt for 7 h. The reaction mixture is poured into 20% aqueous HOAc (180 mL), and the resulting white solid is filtered off. This material is recrystallized from methanol then toluene to yield 2.095 g (74%) of the title compound as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].C[O:12][C:13](=[O:28])[CH:14]([O:26][CH3:27])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24]Br)[CH:17]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:24][CH2:23][O:22][C:18]1[CH:17]=[C:16]([CH2:15][CH:14]([O:26][CH3:27])[C:13]([OH:28])=[O:12])[CH:21]=[CH:20][CH:19]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1O
Reactant: COC(=O)C(Cc1cccc(OCCBr)c1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCOc2ccccc2C(C)C)c1)C(=O)O

Procedure:
The title compound was prepared from 2-isopropyl-phenol and 3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 351, Step 1) via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C21H26O5 [M−H]−:357.2.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:21]([O:23][C:24]([C@H:26]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:27][C@@H:28]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:29](Cl)=[O:30])=[O:25])[CH3:22]>O>[CH2:21]([O:23][C:24]([C@H:26]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:27][C@@H:28]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:29]([NH:11][C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:30])=[O:25])[CH3:22]
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Reactant: CCOC(=O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3.3g of O-benzyl-(S)-serine and 1.8 g of sodium carbonate in 30 ml of water at 0° is added to 2.2 g of 4-ethoxycarbonyl-(S,S)-2,4-dibenzylbutyryl chloride and the mixture is stirred at room temperature for 4 hours. The mixture is extracted with ether, and the aqueous layer is acidified with 2N hydrochloric acid. The acidic solution is extracted with ethyl acetate, washed with saturated brine, dried (magnesium sulfate), filtered and concentrated to yield N-[4-ethoxycarbonyl-(S,S)-2,4-di-benzylbutyryl]-O-benzyl-(L)-serine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:19])=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10]2.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:19])=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10]2)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cc2c(C)ccc(OCCO)c2[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(C)ccc(OCCOS(C)(=O)=O)c2[nH]1
Temperature: -10 °C

Procedure:
A mixture of ethyl 7-(2-hydroxyethoxy)-4-methyl-1H-indole-2-carboxylate (1.10 g, 4.18 mmol), triethylamine (0.93 g, 9.19 mmol) and dichloromethane (30 ml) was cooled to −10° C., after which methanesulfonyl chloride (0.57 g, 5.01 mmol) was added dropwise with stirring at −10° C. After completion of the dropwise addition, the resulting mixture was stirred at −10° C. for another 2 hours and the reaction mixture was poured into ice water, followed by extraction with chloroform (three times). The extract solution was washed successively with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium hydrogen-carbonate solution and a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain ethyl 7-(2-methanesulfonyloxyethoxy)-4-methyl-1H-indole-2-carboxylate. This compound was used in the subsequent reaction without further purification.
Reaction SMILES: OC1C=C(OC)C=CC=1[C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][C:20]=1C1C=CC(OC)=CC=1O)=O.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43]([OH:45])=[O:44])=[CH:38][CH:37]=1.[C:46]([O-:49])([O-])=O.[K+].[K+].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[C:43](=[O:45])[O:44][C:24]3[C:19]([C:17]=2[C:11]2[CH:12]=[CH:13][C:14]([OH:16])=[CH:15][CH:10]=2)=[CH:20][CH:21]=[C:22]([O:49][CH3:46])[CH:23]=3)=[CH:40][CH:41]=1
Reactant: COc1ccc(-c2cc(O)ccc2C(=O)c2ccc(O)cc2-c2ccc(OC)cc2O)c(O)c1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(-c3ccc(O)cc3)c(-c3ccc(Cl)cc3)c(=O)oc2c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2-hydroxy-4-methoxyphenyl-4-hydroxyphenyl ketone (2.6 grams, 10.65 mmol), 4-chlorophenylacetic acid (4.0 g, 23.43 mmol), K2CO3 (4.4 g, 31.95 mnol), carbonyldiimidazole (3.8 g, 23.43 m.mol), and 4-dimethylaminopyridine (0.1 g) in 20 mL of DMF was warmed at 90° C. for 5 hours. The reaction mixture was poured into 150 mL of H2O and stirred for 30 minutes. The precipitated product was collected by filtration and the purified desired product was isolated following flash chromatography (2.1 g, 52%, LC/MS=379 (M+H+)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([OH:23])=O)[CH:19]=[CH:20][C:15]=3[O:14][CH:13]=[CH:12]2)(=[O:10])=[O:9])[CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([NH:26][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH:13]=[CH:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:24][CH3:25])(=[O:9])=[O:10])[C:16]=3[CH:17]=2)=[O:23])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1C=COc2ccc(C(=O)O)cc21
Reactant: Nc1ccccc1
Product: COc1ccc(Cl)cc1S(=O)(=O)N1C=COc2ccc(C(=O)Nc3ccccc3)cc21

Procedure:
Reaction of 4-(5-chloro-2-methoxy-benzenesulfonyl)-4H-benzo[1,4]oxazine-6-carboxylic acid with aniline in accordance with the general method of example 30, step 4 produced the title compound. Orange solid, MS (ISP)=455.2 (M−H)−.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([C:42](C)=[CH2:43])[C:38]2=[N:45][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[CH:28][C:29]=2[C:30]2[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:53].[Na+].CC(=O)OCC>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[C:42]([C:39]1[C:38]2=[N:45][C:35]3=[CH:36][N:37]2[C:12]([N:13]2[CH2:14][CH2:15][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]4[CH:25]=[CH:26][C:27]([F:47])=[CH:28][C:29]=4[C:30]4[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=4)[CH2:49][CH2:50]2)=[C:11]([C@H:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[C:7]([O:9][CH3:10])=[O:8])[C:40]=1[CH3:41])(=[O:53])[CH3:43]
Reactant: C=C(C)c1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C(C)=O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,22,28-trimethyl-5-(prop-1-en-2-yl)-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (45 mg, 0.064 mmol, 1 equiv) was dissolved in dioxane (1934 μl) and water (645 μl). To this solution was added sodium periodate (444 mg, 2.076 mmol, 3.5 equiv) and 4% osmium tetraoxide (372 μl, 0.030 mmol, 0.05 equiv). The mixture was stirred at r.t. for 2 hours. Yellow solid was observed in the meantime. To the mixture was added water (20 mL) and EA (20 mL). The aqueous layer was separated. the organic layer was washed by brine, dried over MgSO4, filtered and concentrated to give a yellow oil, which is used as is for the next reaction. LCMS (ESI, M+1): 700.3.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[CH3:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>>[O:15]=[C:10]1[C:9]2[NH:16][CH:17]=[CH:18][C:8]=2[C:7]2[CH:6]=[C:5]([S:2](=[O:3])(=[O:4])[NH:26][C:25]3[CH:24]=[C:23]([CH3:22])[CH:29]=[CH:28][CH:27]=3)[CH:14]=[CH:13][C:12]=2[NH:11]1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: Cc1cccc(N)c1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Product: CCC(=O)[O-]
Product: Cc1cccc(NS(=O)(=O)c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)c1
Yield: 45.9 %

Procedure:
This compound is prepared according to synthesis 25, from 150 mg (0.46 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 59 μL (0.55 mmol) of 3-methylaniline. After purification by chromatography on silica (eluent dichloromethane/methanol 96/4) then trituration in diethyl ether, 45 mg (23%) of 4-oxo-8-m-tolylsulfamoyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(OCC)(=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:13][C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][CH:15]=1)[CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(CBr)n1
Reactant: OB(O)c1cccc(F)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: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Cc2cccc(F)c2)n1
Temperature: 130 °C
Yield: 18.6 %

Procedure:
A mixture of methyl 6-(bromomethyl)picolinate (0.264 g; 1.15 mmol), 3-fluorophenylboronic acid (0.190 g; 1.31 mmol), tetrakis(triphenylphosphine)palladium(0) (0.066 g; 0.057 mmol) and sodium carbonate (0.244 g; 2.30 mmol) in the mixture of water (1 mL) and 1,2-dimethoxyethane (3 mL) was heated at 130° C. in a microwave oven for 20 minutes. The reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent 0 to 6% of ethyl acetate in dichloromethane) to give 0.0524 g (19%) of methyl 6-(3-fluorobenzyl)picolinate as an oily residue.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][NH:15][C:16]([C@:18]2([CH3:40])[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([O:25][CH2:26][CH:27]2[C:39]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])=O)=[CH:9][CH:8]=1>C1(C)C(C)=CC=CC=1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[NH:5][C:16]([C@:18]3([CH3:40])[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([O:25][CH2:26][CH:27]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=4[C:34]4[C:39]3=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:24])=[N:15][CH:14]=2)=[CH:11][CH:12]=1
Reactant: [NH4+]
Reactant: C[C@@]1(C(=O)NCC(=O)c2ccc(Br)cc2)CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: C[C@@]1(c2ncc(-c3ccc(Br)cc3)[nH]2)CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Yield: 48.5 %

Procedure:
A mixture of ammonium acetate (844 mg; 10.97 mmol) and (S)-(9H-fluoren-9-yl)methyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-2-methylpyrrolidine-1-carboxylate (intermediate LS31; 1.00 g; 1.83 mmol) was heated to 140° C. in 25 mL xylene for 2.5 h at which time the reaction mixture was concentrated and loaded with dichloromethane onto a Biotage 40 samplet. Purification via Biotage (5 to 60% ethyl acetate/hexane over 1000 mL with 400 mL hold time) provided (S)-(9H-fluoren-9-yl)methyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-2-methylpyrrolidine-1-carboxylate (intermediate LS32; 469 mg; 49%) as an amber liquid. LC (Cond'n 12): RT=3.09 min; MS: Anal. Calcd. for [M+H]+ C29H26BrN3O2: 528.1. found 528.5.
Reaction SMILES: C(O)C.[O:4]=[CH:5][C@@H:6]([C@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7].[Sn].[CH2:15](Br)[CH:16]=[CH2:17]>O>[CH2:17]([CH:12]([OH:13])[C@@H:10]([C@H:8]([C@@H:6]([CH2:5][OH:4])[OH:7])[OH:9])[OH:11])[CH:16]=[CH2:15]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Reactant: C=CCBr
Agent: [Sn]
Solvent: O
Solvent: CCO
Product: C=CCC(O)[C@H](O)[C@@H](O)[C@H](O)CO
Temperature: 25 °C

Procedure:
A five liter three-necked round bottom flask, equipped with heating mantle, stirrer, nitrogen inlet, and condenser, was charged with 1.8 liters of ethanol, 0.3 liters of water, 300 g (2.00 mole) of D-xylose, 242 g (2.04 mole) of tin powder (−325 mesh), and 242 g (2.00 mole) of allyl bromide. The mixture was stirred and slowly heated to reflux—a significant exotherm and gas evolution was observed at 60° C. The gray suspension was stirred at reflux for three days, in which time the reaction mixture turned an orange/brown color. Heat was removed and the mixture was allowed to cool to room temperature. The reaction was neutralized to pH=7 by adding approximately 400 ml of 5M NaOH aqueous solution. The suspension was filtered to remove solids, and the yellow solution was decolorized with multiple treatments of activated carbon. The activated carbon was removed by filtration, and the solvent was removed by rotary evaporation to isolate a white syrup. Typical yield was 320 g. 1H NMR (300 MHz, D2O, ppm): 2.33-2.39 (m, 2H), 3.55-3.89 (m, 6H), 5.14-5.23 (m, 2H), 5.89 (m, 1H). The syrup was used without further purification.