Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:50])[NH:19][CH2:20][C:21]([N:23]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]([C:34](=[O:42])[NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:25][CH:24]2[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:22])[CH:14]=[CH:15][CH:16]=1)=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:46]([O:45][C:43]([CH:24]1[CH2:25][CH:26]([C:34](=[O:42])[NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:23]1[C:21](=[O:22])[CH2:20][NH:19][C:18](=[O:50])[NH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:9]([OH:10])=[O:8])=[O:44])([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)C1CC(C(=O)Nc2ccccc2)C(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1CC(C(=O)Nc2ccccc2)C(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 91 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 2A, but from 2.6 g of tert-butyl (2RS,4RS,5SR)-1-{2-[3-(3-(benzyloxycarbonyl)phenyl)ureido]acetyl}-5-phenyl-4-(phenylcarbamoyl)pyrrolidine-2-carboxylate and 0.3 g of 10% palladium-on-charcoal in 150 cm3 of ethanol. After treatment, there are obtained 2.05 g of (2RS,4RS,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-4-phenylcarbamoyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid [Rf =0.15; eluent: methylene chloride/methanol (80/20)].
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11](O)=[O:12])[C:4]=2[CH:3]=1.[CH:20]([C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:24]=1[NH2:25])([CH3:22])[CH3:21]>>[CH:30]([C:26]1[CH:27]=[CH:28][CH:29]=[C:23]([CH:20]([CH3:22])[CH3:21])[C:24]=1[NH:25][C:11]([CH:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[CH2:7][O:6][C:5]2[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][C:4]1=2)=[O:12])([CH3:32])[CH3:31]
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Reactant: CC(C)c1cccc(C(C)C)c1N
Product: Cc1ccc2c(c1)C(C(=O)Nc1c(C(C)C)cccc1C(C)C)c1ccccc1CO2
Yield: 94.8 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.20 g of Compound A and 1.00 g of 2,6-diisopropylaniline in place of aniline to obtain 1.85 g of Compound 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:5][CH:4]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[N:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:20](=[O:21])[CH2:19][Cl:18]
Reactant: COc1ccc(Nc2c(Cl)cccc2Cl)cc1
Reactant: O=C(Cl)CCl
Product: COc1ccc(N(C(=O)CCl)c2c(Cl)cccc2Cl)cc1
Yield: 64 %

Procedure:
Under anhydrous conditions, a mixture of N-(4-methoxyphenyl)-2,6-dichloroaniline (20.2 g, 75.4 mmmol) in 175 mL of chloroacetyl chloride is heated at reflux for 1 hour. The excess acid chloride is evaporated in vacuo and the residue partitioned between saturated NaHCO3 solution and ethyl acetate (30 mL each). The organic phase is washed with brine (30 mL) and dried (Na2SO4). Removal of solvent affords an amber oil. Crystallization of the crude oil from methanol affords the title product (16.63 g, 64%, white needles, m.p. 105°-106° C., lit: 127°-128° C. from methanol) as a 1:1 mixture of rotamers.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[C:11]([C:14]1[C:19]([NH2:20])=[C:18]([CH3:21])[C:17]([O:22][CH3:23])=[CH:16][CH:15]=1)(=[O:13])[CH3:12].N1C=CC=CC=1.O=P(Cl)(Cl)Cl.[OH-].[Na+]>C(Cl)Cl.O>[C:11]([C:14]1[C:19]([NH:20][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[O:10])=[C:18]([CH3:21])[C:17]([O:22][CH3:23])=[CH:16][CH:15]=1)(=[O:13])[CH3:12]
Reactant: Cc1cccc(C(=O)O)n1
Reactant: COc1ccc(C(C)=O)c(N)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(C)=O)c(NC(=O)c2cccc(C)n2)c1C
Temperature: -5 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
6-Methylpicolinic acid (1.12 g, 8.167 mmol) was dissolved in dry DCM (100 ml) and kept on an ice-bath. Then, 6-acetyl-3-methoxy-2-methylaniline (1.48 g, 8.17 mmol) and pyridine (6.6 mL, 0.082 mol) were added followed by drop wise addition of POCl3 (1.53 mL, 0.016 mol) over 15 minutes. The resulting solution was stirred at −5° C. for 1 h. Then, water (100 mL) was added carefully and after 5 min of stirring, NaOH (40%, 20 mL) was subsequently added drop wise followed by the separation of the organic layer. The water layer was extracted three times with CH2Cl2, and the combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (Heptane/AcOEt, 3:1) to give the title compound (2.1 g, 86%): m/z=299 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([F:13])[N:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[S:39](Cl)(=[O:41])=[O:40]>C1COCC1>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([F:13])[N:8]=1)[S:39]([C:32]1[CH:33]=[C:34]([F:38])[C:35]([F:37])=[CH:36][C:31]=1[F:30])(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Reactant: COc1ccc(CNc2ccnc(F)n2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccnc(F)n2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Yield: 63.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 15a by using the N-(2,4-dimethoxybenzyl)-2-fluoropyrimidin-4-amine (0.20 g, 0.76 mmol) prepared in Example 24a, LiHMDS (1.0 M in THF, 0.91 mL, 0.91 mmol), 2,4,5-trifluorobenzenesulfonyl chloride (0.19 g, 0.84 mmol) and THF (3.0 mL), to yield the title compound (0.22 g, 63%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:20])[CH:3]=1.CCN(CC)CC.[CH3:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=O.CC(C)(O)C#N.C([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C.C(Cl)Cl>[OH:1][C:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][C:4](=[O:20])[C:3]=1[CH2:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:31]([CH3:32])[CH:30]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: O=C1C=C(O)CC(c2ccccc2)(c2ccccc2)O1
Agent: CC(C)(O)C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cccc(CC2=C(O)CC(c3ccccc3)(c3ccccc3)OC2=O)c1

Procedure:
The title compound was prepared as described in General Method 8 using the following: 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.300 g, 1.13 mmol), Et3N (0.16 mL, 1.15 mmol), 3-methylbenzoyl chloride (0.15 mL, 1.13 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone cyanohydrin (0.05 mL, 0.58 mmol), Et3N (0.32 mL, 2.3 mmol), glacial acetic acid (4.0 mL), sodium cyanoborohydride (0.28 g, 4.5 mmol). Purification was achieved by submitting the final residue to column chromatograpy (SiO2, 100% CH2Cl2 to 1% MeOH in CH2Cl2) to provide a solid (0.223 g, m.p. 57-59° C.). 1H NMR (400 MHz, DMSO-d6) δ 11.112 (bs, 1 H), 7.414-7.270 (m, 10 H), 6.875-6.812 (m, 2 H), 6.429-6.392 (m, 2 H), 3.527 (s, 2 H), 3.409 (s, 2 H), 2.060 (s, 3 H).
Reaction SMILES: CCN(CC)CC.Cl.[NH2:9][OH:10].[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[CH3:23]>O1CCOCC1.CCOC(C)=O>[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[N:9][OH:10])=[CH:17][C:16]=1[CH3:23]
Reactant: COCOc1ccc(C=O)cc1C
Reactant: NO
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCOc1ccc(C=NO)cc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.4 %

Procedure:
Et3N (1.68 mL, 12.0 mmol) and hydroxylamine hydrochloride (320 mg, 4.64 mmol) were added to a solution of 4-(methoxymethoxy)-3-methylbenzaldehyde (620 mg, 3.44 mmol) in 1,4-dioxane (12 mL). The reaction mixture was sonicated for 10 min and stirred at 25° C. for 3 d. The reaction mixture was diluted with EtOAc and successively washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Hexane:EtOAc, 3:1) to provide the title compound (580 mg, 86% yield) as a clear gum.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[O:14][C:15](Br)=[CH:16][CH:17]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[O:14][C:15]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[CH:25]=3)=[CH:16][CH:17]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2]
Reactant: N#CCc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1cccc(F)c1
Product: N#CCc1cccc(NC(=O)c2ccc(-c3cccc(F)c3)o2)c1

Procedure:
The furyl bromide (83) (135 mg, 0.44 mmol) was coupled to 3-fluoro-phenylboronic acid (68 mg, 0.49 mmol) using Method E. The crude residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:22][CH2:21][C:16]3(OCC[O:17]3)[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.Cl>C1COCC1.O.[OH-].[Na+]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:22][CH2:21][C:16](=[O:17])[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2
Reactant: CN1Cc2c(C3CCC4(CC3)OCCO4)ccc(N)c2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1Cc2c(C3CCC(=O)CC3)ccc(N)c2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-amino-4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (1.64 g, 5.42 mmol) in THF (60 mL) was added aqueous 3.0 M HCl (1.81 mL), the resulting mixture was stirred at rt overnight. The mixture to 0° C., diluted with water and basified to pH ˜10 with 1M NaOH. The aqueous mixture was extracted with EtOAc (3×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.11 (d, J=8.34 Hz, 1H), 6.53 (d, J=8.34 Hz, 1H), 5.88 (s, 2H), 4.41 (s, 2H), 3.00 (s, 3H), 2.56 (dt, J=6.06, 14.15 Hz, 2H), 2.21-2.30 (m, 2H), 1.96-2.04 (m, 2H), 1.78-1.91 (m, 2H); MS (ES+): m/z: 260.1517 [MH+]. HPLC: tR=1.06 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([NH:21][S:22]([C:25]2[CH:26]=[C:27]([CH:38]=[CH:39][CH:40]=2)[C:28]([NH:30][CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]2)=[O:29])(=[O:24])=[O:23])=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2.[CH:41](O)=O.C=O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([NH:21][S:22]([C:25]2[CH:26]=[C:27]([CH:38]=[CH:39][CH:40]=2)[C:28]([NH:30][CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][N:33]2[CH3:41])=[O:29])(=[O:24])=[O:23])=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: O=CO
Reactant: COc1ccc(Cl)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(C(=O)NCC3CCCCN3)c2)c1
Agent: C=O
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cl)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(C(=O)NCC3CCCCN3C)c2)c1

Procedure:
A measured amount of 3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(piperidin-2-ylmethyl)benzamide (299 mg, 0.51 mmol, 1 eq) was dissolved in 2.3 mL of DMA. Formic acid (388 ul, 10.28 mmol, 20 eq) was added to solution with stirring followed by the addition of formaldehyde (508 ul of 37% aq. solution). The reaction was then stirred at room temperature overnight. Analysis of an aliquot of the reaction mixture by LCMS indicated the complete consumption of starting material. The reaction was diluted with methanol (2 mL). Preparative reverse-phase HPLC was used to isolate the desired product directly from the crude reaction mixture. A Waters Fractionlynx preparative reverse-phase HPLC; equipped with a Waters SunFire Prep C18, OCD 5 □M, 30×70 mm column and running a 5-100% gradient with a binary solvent system of 25 mM ammonium acetate in water/acetonitrile; was used to carry out the purification. 1H NMR (400 MHz, d6-DMSO): 9.44 (s, 1H), 8.94 (s, 1H), 8.79 (t, 1H), 8.57 (s, 1H), 8.27 (d, 1H), 7.90 (d, 1H) 7.54 (t, 1H), 7.46 (d, 1H), 7.39 (d, 1H), 7.33 (d, 1H), 7.18 (m, 2H), 6.60 (dd, 1H), 3.82 (s, 3H), 3.59 (m, 2H), 3.00 (s, 1H), 2.90 (s, 3H), 1.62 (m, 7H); MS (EI) for C29H31ClN6O4S: 595 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([CH2:26][OH:27])[CH:23]([CH3:24])[CH:22]([CH3:25])[O:21]2)=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2([CH2:26][O:27][S:2]([CH3:1])(=[O:4])=[O:3])[CH:23]([CH3:24])[CH:22]([CH3:25])[O:21]2)=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1OC(CO)(c2ccc(Cl)cc2)C1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1OC(COS(C)(=O)=O)(c2ccc(Cl)cc2)C1C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
0.13 ml (1.68 mmole) of methanesulfonyl chloride, followed by 0.24 ml (1.708 mmole) of triethylamine were added at 0° C. to a solution of 123 mg (0.543 mmole) of 2-(4-chlorophenyl)-3,4-dimethyl-2-hydroxymethyloxetane in 10 ml of methylene chloride, and the resulting mixture was stirred for 4 hours, during which time the reaction temperature was allowed to rise to room temperature. At the end of this time, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, which was then extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel, eluted with a 10:1 by volume mixture of hexane and ethyl acetate, to afford 107 mg (yield 65%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[CH:19][N:18]=1>>[CH3:23][C:22]1[C:17]([O:1][C:2]2[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=2)=[N:18][CH:19]=[C:20]([S:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH:21]=1
Reactant: Cc1cc(S(=O)(=O)c2ccccc2)cnc1Cl
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Product: Cc1cc(S(=O)(=O)c2ccccc2)cnc1Oc1cc(CC(=O)O)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from step (ii).
Reaction SMILES: [F:1][C:2]1[C:3](/[N:9]=[CH:10]/[N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].C(=S)=S.I[CH2:20][CH3:21]>CN(C=O)C>[CH2:20]([N:6]1[CH:7]=[C:2]([F:1])[C:3](/[N:9]=[CH:10]/[N:11]([CH3:13])[CH3:12])=[N:4][C:5]1=[O:8])[CH3:21]
Reactant: CN(C)/C=N/c1nc(O)ncc1F
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: S=C=S
Product: CCn1cc(F)c(/N=C/N(C)C)nc1=O
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 91.6 %

Procedure:
A 25 mL screw-top vial was charged with (E)-N′-(5-fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformimidamide (99.5 mg, 0.540 mmol), DMF (2 mL), and NaH (60% dispersion in mineral oil; 24.5 mg, 0.613 mmol) and was agitated on a rotary shaker at 50° C. for 40 min. After cooling to room temperature, carbon disulfide (0.036 mL, 0.599 mmol) was added, and the reaction mixture was agitated on a rotary shaker at room temperature for 90 min. At this point, iodoethane (0.052 mL, 0.650 mmol) was added, and the reaction mixture was further agitated at room temperature for 3.5 h, whereupon the crude mixture was concentrated in vacuo. The crude material was purified by normal phase chromatography (gradient, 0 to 30% MeOH/CH2Cl2) to afford (E)-N′-(1-ethyl-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)-N,N-dimethylformimidamide (105 mg, 67%) as a white solid: mp 157-160° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.09 (d, J=6.2 Hz, 1H), 3.70 (q, J=7.1 Hz, 2H), 3.20 (s, 3H), 3.07 (s, 3H), 1.18 (t, J=7.1 Hz, 3H); ESIMS m/z 213 ([M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:4]=[N:3][CH:2]=1.[CH:13]([O:15][CH3:16])=O.[H-].[Na+].C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(COC)OC.C(OCC)C.CN(C)C=O>[N:1]1[CH:6]=[C:5]([CH2:7][C:8](=[CH:13][O:15][CH3:16])[C:9]([O:11][CH3:12])=[O:10])[CH:4]=[N:3][CH:2]=1
Reactant: COC(=O)CCc1cncnc1
Reactant: COC=O
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC=C(Cc1cncnc1)C(=O)OC
Reaction time: 2 h

Procedure:
A mixture of methyl 3-(5-pyrimidyl)propionate (13.1 g) and methyl formate (7.1 ml) dissolved in dry dimethoxyethane (20 ml) was added portionwise to a suspension of sodium hydride (60%, 4.0 g) in DME (10 ml) under argon. Reaction initiated rapidly and was stirred for a further 2 h, diluted with dry diethyl ether (50 ml) and filtered. The solid so separated was washed with further diethyl ether (50 ml) and was dried in vacuo to give a solid that was dissolved in dry dimethyl formamide (50 ml) and potassium carbonate (11.3 g) added under argon. A solution of dimethyl sulfate (7.0 ml) was, then added over 1 hour. The mixture was stirred for 18 h and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (200 ml) and water (100 ml). The aqueous layer was re-extracted with ethyl acetate (2×100 ml) and the combined ethyl acetate layers washed with brine (50 ml) and dried over sodium sulfate. The solvent was removed in vacuo to give methyl 2((5-pyrimidyl)methyl)-3-methoxyacrylate (9.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=O)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O.BrC1C=CC(C2N(C3C=CC(Cl)=CC=3)C(=O)C3C=NN(C4C=CC=C(SC)C=4)C=3N=2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([Cl:20])=[N:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: CSc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Br)cc4)nc32)c1
Solvent: Cc1ccccc1
Product: ClC(=Nc1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 170 °C

Procedure:
4-Bromo-N-(4-chloro-phenyl)-benzimidoyl chloride is prepared by heating 4-bromo-N-(4-chloro-phenyl)-benzamide (16.5 g, 53.0 mmol) and thionyl chloride (140 mL) for 1 h. The clear solution is concentrated and the residue obtained is coevaporated with toluene (100 mL). Then 5-amino-1-(3-methylsulfanyl-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester (1, 9.8 g, 35.33 mmol) is added and the resulting mixture is heated to 170° C. with out solvent for 6 h. The crude product obtained is purified by column chromatography (6).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[CH2:11](OC=C)[CH3:12]>C([O-])(=O)C.[Hg+]>[CH:11]([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1)=[CH2:12]
Reactant: OCCc1ccc(O)cc1
Reactant: C=COCC
Agent: CC(=O)[O-]
Agent: [Hg+]
Product: C=COCCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
4-Hydroxyphenethyl alcohol of formula 3a (15.0 g, 108.0 mmol) was added to ethylvinyl ether of formula 4(200 ml) and stirred for 20 minutes. After cooling to 0° C., mercury acetate (3.4 g, 10.8 mmol) was added and the reaction mixture was stirred for 24 hrs at room temperature. After evaporating solvent, the residue was purified by fresh column chromatography on silica gel (hexane/ethylacetate=5/1, v/v) to obtain pale yellow liquid of the desired product, 4-(2-vinyloxyethyl)phenol of formula 5a (11.0 g, 65 mmol, yield 60%).
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:10][O:9][P:6]([O:7][CH2:8]1)[O:5][CH2:4]2.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:6]12[O:9][CH2:10][C:3]([CH2:2][O:1][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH2:8][O:7]1)[CH2:4][O:5]2
Reactant: OCC12COP(OC1)OC2
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OCC12COP(OC1)OC2)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
16.4 g (0.1 mol) of 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2,2,2]octane are dissolved in 150 ml of toluene by warming. 19.6 g (0.1 mol) of benzoyl chloride are added dropwise at room temperature, followed by 10.1 g (0.1 mol) of triethylamine. The temperature is kept at 30 C by means of an ice bath. After the dropwise addition is complete, the mixture is stirred for 2 hours at 60°C and is then heated to the boil for a short time and filtered while hot from triethylamine hydrochloride. The filtrate is cooled, whereupon the product is precipitated. After filtering and drying, benzoic acid 1-phospha-2,6,7-trioxabicyclo[2,2,2]oct-4 -yl-methyl ester (Stabiliser No. 1) of melting point 160°C is obtained. After recrystallisation from ethanol or isopropanol the product forms long, snow-white needles. If in this example, the benzoyl chloride is replaced by an equivalent quantity of one of the substituted benzoic acid chlorides in Table 1 below, an otherwise identical procedure gives benzoic acid 1-phospha-2,6,7-trioxabicyclo[2,2,2]oct-4-yl methyl esters substituted at the nucleus, the melting points of which are shown.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][N:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])(=[O:11])=[O:10])[S:5][CH:6]=1.[C:23]([NH:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29])([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([N:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:7][C:4]1[S:5][CH:6]=[C:2]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([S:28]([NH:27][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:29])=[O:30])[CH:32]=2)[CH:3]=1)(=[O:11])=[O:10]
Reactant: CC(C)CN(Cc1cc(Br)cs1)S(=O)(=O)c1ccccc1Cl
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(C)CN(Cc1cc(-c2cccc(S(=O)(=O)NC(C)(C)C)c2)cs1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 1, step 3, N-(4-bromo-thiophen-2-ylmethyl)-2-chloro-N-isobutyl-benzenesulfonamide (example 14, step 2) was reacted with 3-tert-butylsulfamoyl-benzeneboronic acid (CAS [221290-14-8]), Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct in dioxane/water to give 2-chloro-N-isobutyl-N-[4-(3-tert-butylaminosulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as an off-white solid. MS: 553.6 ([M−H]−)
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>[Fe].C(O)(=O)C>[C:1]1([S:7]([NH:10][C:11](=[O:21])[C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NS(=O)(=O)c1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1
Reaction time: 12 h

Procedure:
27.2 g of the thus obtained N-(benzenesulfonyl)-p-nitrobenzamide, 270 g of water, and 5.4 g of glacial acetic acid were charged in a 1,000-ml reaction flask, 54 g of iron powder was slowly added, and a reductive reaction was carried out for 12 hours. The reaction solution was made alkaline with sodium carbonate and filtered. The transparent filtrate was acidified with acetic acid to obtain 19.8 g of N-(benzenesulfonyl)-p-aminobenzamide.