Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:19]C1CC(C(C)C)CCC1=O>>[CH2:1]([O:3][C:4]([C:6]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH2:8][C:9](=[O:12])[CH:10]([Br:19])[CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccccc2)CCC(=O)CC1
Reactant: CC(C)C1CCC(=O)C(Br)C1
Product: CCOC(=O)C1(c2ccccc2)CCC(=O)C(Br)C1

Procedure:
The bromination of 4-oxo-1-phenyl-cyclohexane carboxylic acid ethyl ester takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@:15]2([O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]2[OH:18])[OH:16])=[CH:11][C:10]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]2[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]2)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(OCC)(=O)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@:15]2([O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]2[OH:18])[OH:16])=[CH:11][C:10]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cc3cc([C@@]4(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(OC4CCNCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2 mL trifluoroacetic acid are added to a solution of 0.19 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(1-tert-butyloxycarbonylpiperidin-4-yloxy)-benzyl]-benzene in 4 mL dichloromethane. The solution is stirred for 1.5 h at ambient temperature and then diluted with ethyl acetate. The resulting solution is treated with aqueous potassium carbonate solution and the organic phase is separated. The remaining basic aqueous phase is extracted with ethyl acetate and the combined organic phases are dried over sodium sulfate. The solvent is removed under reduced pressure to yield the product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:2]1.C(N(C(C)C)C(C)C)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>ClCCl.CN(C)C=O>[C:31]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:2]1)(=[O:33])[CH3:32]
Reactant: NS(=O)(=O)c1ccc(NCC2CNCCO2)c([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCOC(CNc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of EXAMPLE 415B (145 mg) and N-ethyl-N-isopropylpropan-2-amine (120 μl) in anhydrous dichloromethane (5 mL) and N,N-dimethylformamide (2 mL) was cooled with an ice bath and acetic anhydride (56 μl) was added dropwise. The mixture was stirred at room temperature for 3 hours and concentrated to dryness. The residue was triturated with water. The resulting solid was dried under vacuum to give the title compound.
Reaction SMILES: [S:1]([C:5]1[CH:11]=CC(C)=CC=1)([O-])(=O)=O.O=C1[CH2:18][N:17](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:16][C:15]2C=CSC1=2.[CH2:32]([OH:34])[CH3:33].C1CCCCC1>>[OH:34][C:32]1[CH:18]=[N:17][CH:16]=[C:15]2[S:1][CH:5]=[CH:11][C:33]=12
Reactant: CCO
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)N2CC(=O)c3sccc3C2)cc1
Solvent: C1CCCCC1
Product: Oc1cncc2sccc12
Yield: 78 %

Procedure:
This compound is prepared according to the procedure of Example 1(c), from the tosylate described in (b) above (Yield: 78%). White crystals; M.p.=206° C. (ethanol-cyclohexane).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([OH:26])=[O:25].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].C([O-])(O)=O.[Na+]>C1COCC1>[C:28]([C:23]1[S:19][C:20]([C:24]([OH:26])=[O:25])=[CH:21][CH:22]=1)([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)Cl
Reactant: O=C(O)c1cccs1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(C(=O)O)s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.1 %

Procedure:
To a solution of diisopropylamine (3.6 mL, 25.75 mmol) in 10 mL of THF at -78° C. under argon was added a 1.6M solution of n-butyllithium in hexane (16.1 mL, 25.75 mmol). The mixture was stirred for 15 min, and a solution of 2-thiophenecarboxylic acid 34 (1.5 g, 11.705 mmol) (2-thiophenecarboxylic acid 34 is readily available from Aldrich) in 5 mL of THF was added slowly. The mixture was stirred for 15 min, and ethyl chloroformate (2.7 mL, 28.33 mmol) was added. The mixture was stirred for 30 min at -78° C., and warmed to 0° C. for another 30 min. The reaction mixture was poured into saturated aqueous NaHCO3, and washed with 80% ethyl acetate/hexane. The aqueous layer was acidified with acetic acid and extracted with 80% ethyl acetate/hexane. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated to afford a yellow solid. Flash chromatography yielded the desired acid 35 (1.76 g, 75%) as a white solid: m.p. >300° C. The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])C.[NH2:20][C:21]1[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:22]=1[CH:23]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:29][C:27]1[CH:28]=[C:21]2[C:22]([CH:23]=[C:5]([N:6]3[C:7](=[O:16])[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:14]3=[O:15])[CH:4]=[N:20]2)=[CH:25][CH:26]=1
Reactant: Nc1cc(Br)ccc1C=O
Reactant: CCOC(CN1C(=O)c2ccccc2C1=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1cnc2cc(Br)ccc2c1
Yield: 45.3 %

Procedure:
A mixture of 2-(2,2-diethoxyethyl)isoindoline-1,3-dione (3.16 g, 12.00 mmol), 2-amino-4-bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (1.902 g, 10.00 mmol) in toluene (60 mL) was heated under reflux using Dean-Stark apparatus overnight. A very dark/black solid precipitated overnight and was collected, washed with toluene and hexanes, then dissolved in chloroform fortified with DMF. The mixture was washed with aq. NaHCO3 solution (×2), ensuring any precipitate was dissolved in additional chloroform during separation. The organic layer was dried (sodium sulfate) and evaporated onto silica gel. Purification by flash chromatography (0-2% methanol in dichloromethane) afforded the title compound (1.6 g, 45%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.05 (d, 1 H), 8.57 (d, J=2.3 Hz, 1 H), 8.35 (d, J=1.8 Hz, 1 H), 8.11 (d, J=8.6 Hz, 1 H), 8.09-8.02 (m, 2 H), 8.02-7.93 (m, 2 H), 7.87 (dd, J=1.9, 8.7 Hz, 1 H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1.C1(P(C2C=CC=CC=2)(O[NH2:24])=O)C=CC=CC=1.O>O1CCCC1.CN1CCCC1=O>[NH2:24][N:5]1[CH:6]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:8]=[C:4]1[CH3:3]
Reactant: Cc1nc(-c2ccccc2)c[nH]1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)cn1N
Temperature: 25 °C

Procedure:
7.92 g (171 mmol) of sodium hydride (55-60 percent dispersion in oil) are washed with absolute tetrahydrofuran. A solution of 13.2 g (83 mmol) of 2-methyl-4-phenylimidazole in 356 ml of N-methylpyrrolidone is added dropwise at 0°. The mixture is subsequently stirred at room temperature until the evolution of gas is no longer observed. 39.6 g (171 mmol) of O-diphenylphosphinylhydroxylamine are added portionwise thereto and the mixture is stirred for a further 18 hours. 400 ml of water are added thereto. The mixture is stirred for 1 hour and extracted four times with 1300 ml of methylene chloride each time. The extract is dried over sodium sulphate and evaporated. The residue is place on a column loaded with 700 g of silica gel (particle size 0.063-0.200 mm) amnd the product is eluted with methylene chloride/ethanol (98:2). The oil (N-amino-2-methyl-4-phenylimidazole) obtained after concentration is dissolved with 1150 ml of methylene chloride and treated with 13.94 g (60 mmol) of O-diphenylphosphinylhydroxylamine. After stirring for 3 days a further 13.94 g (60 mmol) of O-diphenylphosphinylhydroxylamine are added thereto and the mixture is stirred for a further 24 hours. The mixture is concentrated and the residue is placed on a column loaded with Amberlite IRA 400 (chloride). Elution is carried out with water. The aqueous solution is evaporated and the residue is placed on a column loaded with 300 g of silica gel (particle size 0.063-0.200 mm). The product is eluted with methylene chloride/ethanol (1:9). From the eluate there is obtained 1,3-diamino-2-methyl-4-phenylimidazolium chloride of melting point 162°-163°.
Reaction SMILES: [F:1][C:2]1[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1.N1C=CC=CC=1.FC(F)(F)S([O:43][S:44]([C:47]([F:50])([F:49])[F:48])(=[O:46])=[O:45])(=O)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([O:43][S:44]([C:47]([F:48])([F:49])[F:50])(=[O:45])=[O:46])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: COC(=O)c1cn2c3c(c(OS(=O)(=O)c4ccc(C)cc4)c(F)cc3c1=O)CCN2C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cn2c3c(c(OS(=O)(=O)C(F)(F)F)c(F)cc3c1=O)CCN2C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.8 g of the compound (169) obtained in Example 46 was added to 10 ml of pyridine, and while cooling on ice, 2.35 ml of trifluoromethanesulfonic anhydride was added to the solution through 20 minutes. The solution was stirred for 24 hours at room temperature. 200 ml of chloroform was added to the solution, and the solution was washed with aqueous 5% citric acid solution. The organic layer was separated and after drying over magnesium sulfate, the solvent was removed by distillation. To the residue, ethanol was added, and the solid matter was filtered off and purified by column chromatography (silica gel, eluent solvent; chloroform:ethyl acetate=1:1). The solid matter was filtered off and washed with isopropyl ether to obtain 1.2 g of the subject compound (170).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH:29]([CH3:35])[CH2:30][CH2:31][CH2:32][C:33]#[CH:34]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[CH2:15]([O:14][C:11]1[CH:10]=[N:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]#[C:33][CH2:32][CH2:31][CH2:30][CH:29]([O:28][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][O:22]3)[CH3:35])=[CH:3][CH:4]=2)=[N:13][CH:12]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1ccc(-c2ncc(OCc3ccccc3)cn2)cc1
Reactant: C#CCCCC(C)OC1CCCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CC(CCCC#Cc1ccc(-c2ncc(OCc3ccccc3)cn2)cc1)OC1CCCCO1
Temperature: 90 °C

Procedure:
In a reactor equipped with a stirrer and a thermometer, 2-(4-bromophenyl)-5-benzyloxypyrimidine, 6-tetrahydropyranyloxy-1-heptyne, dichlorobis(triphenylphosphine)palladium, copper iodide, triphenylphosophine and triethylamine are charged and heated up to 90° C. to carry out a reaction for 8 hours. After extraction with toluene and washing with water, the mixture is evaporated under reduced pressure. A resulting residue is purified by silica gel column chromatography to obtain 5-benzyloxy-2-[4-(6-tetrahydropyranyloxy-1-heptynyl)phenyl]pyrimidine.
Reaction SMILES: Br[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C1COCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:13][C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][CH:15]=1)[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=c1c(Br)coc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(-c2cccc(Cl)c2)coc2ccccc12
Yield: 50.1 %

Procedure:
Prepared according to general procedure using 3-bromochromone (338 mg, 1.5 mmol), 3-chlorophenylboronic acid (256 mg, 1.65 mmol), K2CO3 (622 mg, 4.5 mmol), PdCl2(PPh3)2 (45 mg, 0.045 mmol), THF (3 mL) and water (1.5 mL). Purified by flash column chromatography (SiO2, 10% EtOAc/Hex) to afford 38 (193 mg, 50%) as a white solid. Analytical data for isoflavone 38: 1H NMR (500 MHz, CDCl3) δ 8.33 (d, J=9.5 Hz, 1H), 8.06 (s, 1H), 7.73 (app t, J=8.5 Hz, 1H), 7.60 (s, 1H), 7.59-7.45 (m, 3H), 7.39 (d, J=7 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 176.1, 156.4, 153.6, 134.6, 134.1, 133.9, 130.0, 129.2, 128.6, 127.4, 126.7, 125.7, 124.7, 124.5, 118.4; LCMS: Mass calculated for C15H9ClO2, [M+H]+, 257. Found 257.
Reaction SMILES: I[C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][NH:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[C:27]1(/[CH:33]=[CH:34]/B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[N:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7]([NH:6][O:5][CH2:4][C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=2[CH:34]=[CH:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:22])=[CH:17][CH:18]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: O=C(NOCc1ccccc1I)c1ccccc1NCc1ccncc1
Product: O=C(NOCc1ccccc1C=Cc1ccccc1)c1ccccc1NCc1ccncc1

Procedure:
Starting materials: N-(2-Iodo-benzyloxy)-2-[(pyridin-4-ylmethyl)-amino]-benzamide (example 360) and trans-2-phenylvinylboronic acid (Aldrich).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:26]([CH:37]([CH3:39])[CH3:38])=[CH:25][C:10]=1[C:11]([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:22]([OH:24])=O)[CH:19]=2)[CH2:14]1)=[O:12])C1C=CC=CC=1.C(Cl)CCl.[CH:44]1[CH:45]=[CH:46][C:47]2N(O)N=N[C:48]=2[CH:49]=1.CCN(CC)CC.Cl.[CH3:62][NH:63][O:64][CH3:65]>CN(C=O)C>[CH3:65][O:64][N:63]([CH3:62])[C:22]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([C:11](=[O:12])[C:10]1[CH:25]=[C:26]([CH:37]([CH3:39])[CH3:38])[C:27]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:28][C:9]=1[O:8][CH2:1][C:49]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:21]2)=[O:24]
Reactant: CNOC
Reactant: On1nnc2ccccc21
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc(C(=O)O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc2c(c1)CN(C(=O)c1cc(C(C)C)c(OCc3ccccc3)cc1OCc1ccccc1)C2
Yield: 96.1 %

Procedure:
A solution of 2-(2,4-bis-benzyloxy-5-isopropyl-benzoyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid (Preparation D6) (1.76 g, 3.39 mmol), EDC (0.78 g, 4.06 mmol), HOBT (0.55 g, 4.06 mmol), Et3N (1 ml, 6.78 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.36 g, 3.72 mmol) in DMF (20 ml) was stirred at room temperature for 48 hours, then evaporated under vacuum. The crude material was dissolved in ethyl acetate and extracted twice with saturated NaHCO3, organics washed with brine, dried (MgSO4), filtered then evaporated to give 1.84 g of 2-(2,4-bis-benzyloxy-5-isopropyl-benzoyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid methoxy-methyl-amide. MS: [M+H]+ 563.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]3[C:29]([C:30](=[O:33])[NH:31][CH3:32])=[C:28]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)[O:27][C:7]3=[N:8][C:9]=2[N:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19](S(C)(=O)=O)[C:20]([OH:22])=[O:21])[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3][CH2:2]1.[O:41]=[C:42](C)[CH2:43]C(OCC)=O.BrCCCCN(C1N=C2OC(C3C=CC(C)=CC=3)=C(C(NC)=O)C2=CC=1C1CC1)S(C)(=O)=O>>[CH:1]1([C:4]2[CH:5]=[C:6]3[C:29]([C:30](=[O:33])[NH:31][CH3:32])=[C:28]([C:34]4[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=4)[O:27][C:7]3=[N:8][C:9]=2[N:10]([CH2:15][CH2:16][CH2:17][CH2:18]/[C:19](=[C:42](/[OH:41])\[CH3:43])/[C:20]([OH:22])=[O:21])[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(C)=O
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCCC(C(=O)O)S(C)(=O)=O)S(C)(=O)=O)c(C3CC3)cc12
Agent: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCCBr)S(C)(=O)=O)c(C3CC3)cc12
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCC/C(C(=O)O)=C(\C)O)S(C)(=O)=O)c(C3CC3)cc12

Procedure:
Prepared similarly to Example 46 6-(N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(p-tolyl)furo[2,3-b]pyridin-6-yl)methylsulfonamido)-2-(methylsulfonyl)hexanoic acid, by using ethyl 3-oxobutanoate in the alkylation with 6-(N-(4-bromobutyl)methylsulfonamido)-5-cyclopropyl-N-methyl-2-(p-tolyl)furo[2,3-b]pyridine-3-carboxamide, followed by hydrolysis.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+].[CH3:28]N1C(=O)CCC1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:21]3[CH:20]=[N:19][C:18]([O:17][CH2:16][CH3:28])=[CH:23][CH:22]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CN1CCCC1=O
Reactant: C=Cc1ccc(OC)nc1
Agent: [K+]
Agent: [OH-]
Product: CCOc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 2-methoxy-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][NH:14][CH2:15][CH2:16][OH:17]>C1(C)C(C)=CC=CC=1>[CH3:13][N:14]([CH2:15][CH2:16][OH:17])[CH2:9][CH2:8][C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CNCCO
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Solvent: Cc1ccccc1C
Product: CN(CCO)CCc1ccc([N+](=O)[O-])cc1
Yield: 90.1 %

Procedure:
A mixture of 4-nitrophenethyl bromide (11.5 g) and N-methylethanolamine (8.25 g) in xylene (100 ml) was stirred at reflux for 16 hours. After evaporation, the residue was partitioned between 5% aqueous sodium bicarbonate and methylene chloride. The organic liquors were washed with saturated aqueous brine, dried (MgSO4), filtered and evaporated to give an orange oil (10.1 g). Chromatography on silica ("Kieselgel 60"--Trade Mark) eluting with ethyl acetate followed by collection and evaporation of suitable fractions gave the title compound as a yellow oil, (7.5 g).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@@H:6]1Br)(=O)C.[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1SC(N)=[NH2+])(=[O:28])C.C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1SCC#N)(=O)C>>[O:20]=[CH:19][C@@H:8]([C@H:9]([C@H:10]([C@@H:5]([CH2:6][OH:28])[OH:4])[OH:11])[OH:15])[OH:7]
Reactant: CC(=O)OC[C@H]1O[C@@H](SC(N)=[NH2+])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](SCC#N)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Br-]
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO

Procedure:
The galactose coupling agent 2-imino-2-methoxyethyl-1-thio-β-D-galactopyranoside (9) was prepared starting from 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide (6) in 3 steps via the intermediates 2-S-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-2-thiouronium bromide (7) and cyanomethyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranoside (8) as shown in FIG. 5.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:29]>ClCCl.O>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([F:29])=[O:6]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(F)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
To a stirred mixture of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (12 g, 30.5 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, in dichloromethane (70 mL) at 0° C. was added pyridine (2.5 mL, 30.8 mmol) followed by dropwise addition of cyanuric fluoride (2.8 mL, 33.6 mmol). The reaction mixture was stirred at 0° C. for 10 minutes and then warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with water and extracted with dichloromethane (100 mL). The aqueous layer was extracted once with dichloromethane (50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude product as a brownish solid. Crude product was purified by flash chromatography (plug, 25% ethyl acetate in hexanes) to afford 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride as a beige solid (11.8 g, 97% yield). 1H NMR (400 MHz, CD3OD): 8.41 (s, 1H), 7.80-7.81 (m, 1H), 7.52 (dd, 1H), 7.43-7.47 (m, 1H), 6.96-7.03 (m, 1H), 6.85-6.92 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]2[CH2:41][CH2:40][C:17]3[N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:19]=[N:20][C:16]=3[CH2:15]2)=[O:11])=[CH:4][CH:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]2[CH2:41][CH2:40][C:17]3[NH:18][CH:19]=[N:20][C:16]=3[CH2:15]2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(CCc1ccc(Cl)cc1)NCC1CCc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Solvent: O
Solvent: CC(=O)O
Product: O=C(CCc1ccc(Cl)cc1)NCC1CCc2[nH]cnc2C1
Temperature: 90 °C

Procedure:
A solution of a mixture of 3-(4-chlorophenyl)-N-((1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)methyl)propionamide and 3-(4-chlorophenyl)-N-((3-triphenylmethyl-4,5,6,7-tetrahydro-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)methyl)propionamide (0.69 g, 1.23 mmol) in acetic acid (5 ml) and water (0.6 ml) was heated to 90° C. for 1.5 hours. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 0.42 g of the title compound.
Reaction SMILES: C1COC2C=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19]C4C=CC=C(O)C=4)[N:13]=3)=CC=2O1.ClC1N=C(NCC[S:37][CH2:38][C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[Cl:46])C(F)=CN=1.[O:48]1C2C=CC(N)=CC=2[O:51][CH2:50][CH2:49]1>>[Cl:46][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]([F:45])[C:39]=1[CH2:38][S:37][CH2:6][CH2:5][NH:11][C:12]12[O:51][CH2:50][CH2:49][O:48][N:13]1[C:14]([NH2:19])=[N:15][CH:16]=[C:17]2[F:18]
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: Fc1cnc(Cl)nc1NCCSCc1c(F)cccc1Cl
Reactant: Nc1ccc2c(c1)OCCO2
Product: NC1=NC=C(F)C2(NCCSCc3c(F)cccc3Cl)OCCON12

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-[2-[(2-chloro-6-fluorobenzyl)thio]ethyl]-5-fluoro-4-pyrimidineamine and 1,4-benzodioxan-6-amine were reacted to yield N4-[2-[(2-chloro-6-fluorobenzyl)thio]ethyl]-N2-(3,4-ethylenedioxy)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.09 (bs, 1H), 7.94 (bs, 1H), 7.87 (d, 1H, J=4.2 Hz), 7.34-7.30 (m, 2H), 7.24-7.18 (m, 2H), 7.01 (dd, 1H, J=2.4 and 8.7 Hz), 6.68 (d, 1H, J=8.7 Hz), 4.11 (s, 4H), 3.83 (d, 2H, J=1.2 Hz), 3.63-3.56 (m, 2H), 2.74 (t, 2H, J=7.5 Hz); LCMS: ret. time: 25.17 min.; purity: 92%; MS (m/e): 466 (MH+).