Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@H]1CCOC(=O)N1C(=O)[C@@H:16]([C@H:21]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:22]1[CH:23]=[N:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[CH2:17][CH2:18][C:19]#[CH:20])C1C=CC=CC=1.[O:38]1[CH2:42]CCC1.[OH:43]O.[OH-].[Na+]>O>[Si:30]([O:29][C@H:21]([C:22]1[CH:23]=[N:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[C@@H:16]([CH2:17][CH2:18][C:19]#[CH:20])[C:42]([OH:38])=[O:43])([C:33]([CH3:34])([CH3:36])[CH3:35])([CH3:32])[CH3:31]
Reactant: C1CCOC1
Reactant: OO
Reactant: C#CCC[C@@H](C(=O)N1C(=O)OCC[C@@H]1Cc1ccccc1)[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCC[C@@H](C(=O)O)[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
To a stirred solution of 37 g (70 mmol) of (4S)-4-benzyl-3-{(2R)-2-[(S)-{[tert-butyl(dimethyl)silyl]oxy}(6-chloropyridin-3-yl)methyl]hex-5-ynoyl}-1,3-oxazinan-2-one from Step C above in 520 mL of a 3 to 1 mixture of anhydrous tetrahydrofuran to water at 0° C. under an atmosphere of nitrogen was added 30 mL (350 mmol) of a 35% aqueous hydrogen peroxide solution at a rate slow enough to keep the internal temperature below 3° C. Next, 140 mL (140 mmol) of a 1.0 M aqueous sodium hydroxide solution was added at a rate slow enough to keep the internal temperature of the reaction below 5° C. After complete addition the resulting mixture was stirred for 18 h at 0° C. then quenched with a solution of 350 mL (420 mmol) of a 1.2 M aqueous sodium sulfite solution at a rate slow enough to keep the internal temperature of the mixture below 15° C. All volatiles were removed in vacuo and the remaining aqueous phase was cooled to 0° C. and acidified with a 2.5 M aqueous hydrogen chloride solution until a pH of 3 was achieved. The aqueous phase was then extracted with ethyl acetate (3×200 mL) and the combined organics were washed with brine (10 ml), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 15% ethyl acetate and 3% acetic acid in hexanes to afford the title compound as a white solid (16 g, 62%). LC-MS: m/z (ES) 368.2 (MH)+.
Reaction SMILES: C(OC([P:9]([C:14]([F:19])([F:18])[CH2:15][CH2:16][CH3:17])(=[O:13])[O:10][CH2:11][CH3:12])(OCC)C)C.C(O)C.C[Si](C)(C)Cl>O1CCCC1>[CH2:11]([O:10][P:9]([C:14]([F:19])([F:18])[CH2:15][CH2:16][CH3:17])[OH:13])[CH3:12]
Reactant: CCCC(F)(F)P(=O)(OCC)C(C)(OCC)OCC
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC(F)(F)P(O)OCC
Temperature: 25 °C

Procedure:
To 8.2 g (27.1 mMol) of ethyl 1,1-diethoxyethyl(1,1-difluorobutyl)phosphinate in 81 ml of dry tetrahydrofuran are added, with stirring at room temperature, 9 ml of ethanol and 5.1 ml (40.7 mMol) of trimethylchlorosilane. After 5 hours of stirring the reaction mixture is evaporated and the remaining oil is chromatographed on a silica gel column eluting with ether. The product-containing fractions are collected and the solvent is evaporated leaving 1,1-difluorobutylphosphonous acid ethyl ester as colorless oil, Rf=0.4 (CH2Cl2 /CH3COOH, 95+5).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=[C:10]([CH:12]=[O:13])[CH3:11])[CH3:2].[BH4-].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[CH2:12][OH:13])[CH3:2]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C=C(C)C=CC=C(C)CO
Temperature: 10 °C
Reaction time: 2 h

Procedure:
36 g. of 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester are dissolved in 600 ml. of absolute ethanol. The solution is treated portionwise with 1.8 g. of sodium borohydride. The mixture is stirred for 2 hours at 10° C., then poured onto ice water and 3 n aqueous hydrochloric acid and extracted with ether. The ether extract is washed successively with water, a saturated aqueous sodium bicarbonate sodium and once more with water, dried over sodium sulfate and evaporated. There is obtained 8-hydroxy-3,7-dimethyl-octa-2,4,6-trien-1-oic acid ethyl ester, which is processed further as follows:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][C:19]2[CH:23]=[C:22](OC(C)C)[NH:21][N:20]=2)=[N:4][C:5]([NH:8][CH:9]([C:11]2[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])=[N:6][CH:7]=1.[CH:28]1(C2NN=C(NC3C(F)=CN=C(N[C@H](C4N=CC(F)=CN=4)C)N=3)C=2)CC1.CCN(C(C)C)C(C)C>CCCCO>[Cl:1][C:2]1[C:3]([NH:18][C:19]2[CH:23]=[C:22]([CH3:28])[NH:21][N:20]=2)=[N:4][C:5]([NH:8][CH:9]([C:11]2[N:12]=[CH:13][C:14]([F:17])=[CH:15][N:16]=2)[CH3:10])=[N:6][CH:7]=1
Reactant: C[C@H](Nc1ncc(F)c(Nc2cc(C3CC3)[nH]n2)n1)c1ncc(F)cn1
Reactant: CC(C)Oc1cc(Nc2nc(NC(C)c3ncc(F)cn3)ncc2Cl)n[nH]1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(NC(C)c3ncc(F)cn3)ncc2Cl)n[nH]1
Temperature: 180 °C
Yield: 61.9 %

Procedure:
A mixture of rac-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 1, 100 mg), 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 9, 200 mg) and DIPEA (0.150 ml) in n-BuOH (2.5 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated in microwave reactor at 180° C. for 6 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 min) to give 5-chloro-N2-[1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as solid (55 mg). The tile compound was obtained after chiral purification using SFC conditions (Chiralpak AD-H, 20% i-PrOH/80% CO2/0.1% Dimethylethylamine). 1H NMR (300 MHz, DMSO-d6) δ 12.03 (s, 1H) 8.83 (s, 2H) 7.88 (s, 1H) 7.44 (s, 1H) 5.93 (s, 1H) 4.92-5.29 (m, 1H) 2.20 (s, 3H) 1.49 (d, 3H); m/z 350.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:8][NH:9]2)=[CH:5][C:4]=1[C:21]([NH2:23])=[NH:22].CN(C)[CH:26]=[CH:27][CH:28]=O>N1C=CC=CC=1>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)=[N:8][NH:9]2)=[CH:5][C:4]=1[C:21]1[N:23]=[CH:28][CH:27]=[CH:26][N:22]=1
Reactant: CN(C)C=CC=O
Reactant: N=C(N)c1cc2c(/C=C/c3ccc(F)cc3)n[nH]c2cc1F
Agent: Cl
Solvent: c1ccncc1
Product: Fc1ccc(/C=C/c2n[nH]c3cc(F)c(-c4ncccn4)cc23)cc1
Temperature: 120 °C
Reaction time: 7 h

Procedure:
36 mg of 6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxamidine hydrochloride obtained by Example 599 and 15 μl of 3-dimethylaminopropenal were dissolved in 1 mL of pyridine, and stirred at 120° C. for 7 hours. After distilling off the solvent, purification by LC-MS was conducted, to give 0.61 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][Cl:16])=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Cl-:16].[OH:8][C:7]1[C:2]([CH3:1])=[N+:3]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ncccc1O
Reactant: COc1ccc(CCl)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C[n+]2cccc(O)c2C)cc1
Product: [Cl-]

Procedure:
To a suspension of 2-methyl-3-hydroxypyridine (71) (10 g, 91.6 mmol) in toluene (45 mL) was added 4-methyoxybenzyl chloride (72) (12.4 mL, 1 eq). The mixture was refluxed overnight. The solvent was concentrated to about ⅓ of the volume. After cooling, the solid was isolated via filtration and washed with a small amount of toluene to give the desired product, which was used without further purification. 1H NMR (d6-DMSO) δ 8.61 (d, 1H, J=6 Hz), 8.16 (d, 1H, J=8.4 Hz), 7.85 (t, 1H, J=6.9 Hz), 7.28 (d, 2H, J=8.1 Hz), 7.02 (d, 2H, J=8.4 Hz), 5.82 (s, 2H), 3.79 (s 3H), 2.59 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH2:12]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH2:16][CH2:15][O:14][CH2:13]1.C(N(C(C)C)C(C)C)C>CC(O)C>[Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([N:17]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)=[CH:23][CH:22]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cnc(Nc2ccc(N3CCOCC3)cc2)c2ncnn12
Yield: 93.8 %

Procedure:
A mixture of 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (123 mg, 443 μmol), 4-(4-morpholino)aniline (118 mg. 0.664 mmol) and N-ethyldiisopropylamine (116 mL, 0.664 mmol) is heated at reflux in 2-propanol (3 mL) for 4.5 hours. The reaction mixture is evaporated to dryness and the residue partitioned between dichloromethane and citric acid (10%). The organic phase is washed once with water and brine, dried over MgSO4, filtered and evaporated to furnish the title compound (156 mg, 94%) as a yellow solid. 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 3.11 (m, 4H), 3.78 (m, 4H), 6.97 (d, 2H), 7.82 (d, 2H), 7.87 (s, 1H), 8.71 (s, 1H), 9.93 (br s, 1H). LCMS, Rt 3.32 min (96.8%) m/z (APCI) 375 (M+H)+.
Reaction SMILES: C[O-].[Na+].[SH:4][CH2:5][CH2:6][OH:7].Cl[CH2:9][C:10]#[C:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>CO>[CH2:6]([OH:7])[CH2:5][S:4][CH2:9][C:10]#[C:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: OCCS
Reactant: CCCCCCCCC#CCC#CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCCC#CCC#CCSCCO
Reaction time: 0.5 h
Yield: 61 %

Procedure:
1.06 ml of a 30% solution of sodium methoxide in methanol were added dropwise, at room temperature, to a solution of 374 μl of 2-mercaptoethanol in 5 ml of anhydrous methanol, under an inert atmosphere. The mixture was maintained under stirring for 30 min and then added to a solution of 1.2 g of 1-chloro-2,5-tetradecadiyne in 6 ml of methanol, under an inert atmosphere. The mixture was maintained under stirring for 15 hours at room temperature and then the reaction medium was poured over 100 ml of acid water (98 ml of water+2 ml concentrated H2SO4) and then extracted 3 times with ethyl ether. The combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried (Na2SO4), filtered and concentrated under vacuum in a rotary evaporator. The oil thus obtained crystallized on cooling. It was purified by recrystallization from a heptane/pentane mixture and then from a heptane/pentane/diisopropyl ether mixture. 3-Thia-5,8-heptadecadiyn-1-ol was thus isolated in the form of pale yellow flakes with a yield of 61%.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6]1)#[CH:4].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:16][O:15][C:13](=[O:14])[CH2:12][O:10][C:5]1([C:3]#[CH:4])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)CBr
Reactant: C#CC1(O)CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CC1(OCC(=O)OC)CCCC1
Reaction time: 1 h

Procedure:
A mechanically stirred suspension of sodium hydride (60% dispersion in mineral oil, 1.5 g, 38 mmol) in tetrahydrofuran (10 mL) at 0 C. under nitrogen was treated with a solution of 1-ethynylcyclopentanol (5.0 g, 45 mmol) in tetrahydrofuran (20 mL) over 15 minutes. After stirring at 0 C. for 1 hour, the mixture was treated with methyl bromoacetate (5.4 mL, 56 mmol). after stirring at ambient temperature for 16 hours, the mixture was treated with 2M HCl (25 mL) and then treated with ethyl acetate (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, concentrated and used without purification in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:24])(=[O:23])[NH:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:13][C:12]=2[CH3:25])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:33]1([CH2:36][NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH2:34]1>C(O)C>[CH:33]1([CH2:36][N:37]([CH2:38][CH2:39][CH3:40])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:18][CH2:19][CH2:20][O:21][CH3:22])(=[O:24])=[O:23])=[CH:13][C:12]=3[CH3:25])=[O:9])[CH:3]=2)[CH2:35][CH2:34]1
Reactant: CCCNCC1CC1
Reactant: COCCNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Solvent: CC(C)NC(C)C
Solvent: CCO
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(=O)(=O)NCCOC)cc2C)ncn1
Temperature: 160 °C

Procedure:
A solution of 6-chloro-N-(4-(N-(2-methoxyethyl)sulfamoyl)-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 38, 100 mg; 0.26 mmol) and diisopropylamine (91 mL; 0.52 mmol) in ethanol (2.5 ml) was treated with N-(cyclopropylmethyl)propan-1-amine (0.7 ml, 0.33 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:23]([OH:25])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.[F:35][C:36]([F:41])([F:40])[CH2:37][CH2:38]O.C(C=P(CCCC)(CCCC)CCCC)#N.O>C1(C)C=CC=CC=1>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:23]([O:25][CH2:38][CH2:37][C:36]([F:41])([F:40])[F:35])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(O)c2)ncn1)C1CC1
Reactant: OCCC(F)(F)F
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(OCCC(F)(F)F)c2)ncn1)C1CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(6-((6-(2-fluoro-5-methoxyphenyl)-5-hydroxypyridin-3-yl)methoxy)pyrimidin-4-yl)propanoate (57 mg) in toluene (1.2 mL) were added 3,3,3-trifluoro-1-propanol (21 μL) and cyanomethylenetributylphosphorane (64 uL), and the mixture was stirred at 100° C. for 4 hr. After allowing to cool to room temperature, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (53 mg) as a pale-yellow amorphous solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>ClCCl>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])[CH2:16][CH2:15]1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h

Procedure:
A solution of 20.0 g 4-nitrobenzoylchloride in 100 ml dichloromethane is added dropwise to a solution of 12.0 ml of N-methylpiperazine and 30 ml of triethylamine in 600 ml of dichloromethane at ambient temperature. The reaction solution is stirred for one hour, then washed three times with water, dried with sodium sulphate and evaporated to dryness. The residue is stirred with tert-butylmethylether and dried at 40° C.
Reaction SMILES: [Br-:1].[C:2]1([CH2:28][N+:29]2([CH2:41][C:42]3C=CC=C[CH:43]=3)[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][NH+:38]=[CH:37][CH:36]=3)=[CH:31][CH2:30]2)[CH:7]=[CH:6][C:5]([CH2:8][N+:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][N+:18]([CH2:21][C:22]4C=CC=C[CH:23]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Br-].[Br-].[Br-].C([Br:54])C=C>>[Br-:54].[C:2]1([CH2:28][N+:29]2([CH2:41][CH:42]=[CH2:43])[CH:30]=[CH:31][C:32]([C:35]3[CH:36]=[CH:37][NH+:38]=[CH:39][CH:40]=3)=[CH:33][CH2:34]2)[CH:7]=[CH:6][C:5]([CH2:8][N+:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][N+:18]([CH2:21][CH:22]=[CH2:23])=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Br-:1].[Br-:54].[Br-:54]
Reactant: C=CCBr
Reactant: C1=C[N+](Cc2ccccc2)(Cc2ccc(C[n+]3ccc(-c4cc[n+](Cc5ccccc5)cc4)cc3)cc2)CC=C1c1cc[nH+]cc1
Agent: [Br-]
Product: C=CC[n+]1ccc(-c2cc[n+](Cc3ccc(C[N+]4(CC=C)C=CC(c5cc[nH+]cc5)=CC4)cc3)cc2)cc1

Procedure:
Compound 15 was synthesized as described above for compound 14, reflux time 3 h. Allyl bromide (1.97 g, 16.28 mmol), compound 4 (1.0 g, 1.42 mmol). The target compound was isolated as a bright yellow solid. Yield: 0.48 g, 42%. 1H NMR (D2O, 400 MHz): δ (ppm) 9.21-9.23 (4H, d), 9.14-9.16 (4H, d), 8.601 (8H, m), 7.68 (4H, s), 6.19-6.26 (2H, m), 6.03 (4H, s), 5.57-5.67 (2H, quad), 5.37-5.39 (2H, d). 13C NMR (D2O, 100 MHz): δ (ppm) 153.48, 153.04, 148.70, 148.66, 148.65, 148.63, 148.52, 148.46, 148.38, 136.95, 133.21, 132.33, 130.13, 129.89, 126.60, 67.01, 66.54.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4]Cl.[Mg].[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([Cl:20])[N:14]=1>BrCCBr>[Cl:12][C:13]1[N:14]=[C:15]([Cl:20])[CH:16]=[C:17]([CH2:4][C:3]2[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=2[Cl:10])[N:18]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: ClCc1c(Cl)cccc1Cl
Agent: [Mg]
Solvent: BrCCBr
Product: Clc1cc(Cc2c(Cl)cccc2Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A solution of 2,6-dichlorobenzylchloride (0.102 mol) in 1,1-diethylether (10 ml) was added dropwise to magnesium (0.102 mol) in 1,1-diethylether (60 ml). The reaction was initiated by adding 2 drops of 1,2-dibromoethane. After most of magnesium disappeared, 2,4,6-trichloropyrimidine (0.051 mol) in 1,1-diethylether (30 ml) was added. The mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by flash column chromatography over silica gel (eluent: CH2Cl2/hexane ½). The desired fractions were collected and the solvent was evaporated, yielding 3.3 g of (21%) 2,4-dichloro-6-[(2,6-dichloro-phenyl)methyl]pyrimidine (interm. 1; m.p.: 106-107° C.).
Reaction SMILES: ICC.[CH3:4][O-:5].[Na+].[CH2:7]([O:9][C:10]1[CH:18]=[CH:17][C:16](OC)=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13])[CH3:8].[CH3:21][OH:22]>>[C:4]([C:16]1[CH:17]=[CH:18][C:10]([O:9][CH2:7][CH3:8])=[C:11]([CH:15]=1)[C:12]([NH2:14])=[O:13])([O:22][CH3:21])=[O:5]
Reactant: CO
Reactant: C[O-]
Reactant: CCOc1ccc(OC)cc1C(N)=O
Agent: [Na+]
Solvent: CCI
Product: CCOc1ccc(C(=O)OC)cc1C(N)=O

Procedure:
5-Carbomethoxy-2-ethoxybenzamide (m.p. 159°-161° ) was prepared from 5-carbomethoxysalicylamie, iodoethane, and sodium methoxide in methanol in a manner analogous to that described for the preparation of 2-ethoxy-5-methoxybenzamide in Preparation 14A.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1.[C:26]1([Mg]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)(=O)C.CCCCCC>O1CCCC1.OP(O)=O.O[Mo](O)(=O)=O>[OH:1][C@@H:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[C:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)c1cccc(C#Cc2ccccc2)c1
Agent: O=[Mo](=O)(O)O
Agent: O=[PH](O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](c1cccc(C#Cc2ccccc2)c1)[C@@H](O)c1ccccc1
Reaction time: 1 h
Yield: 53 %

Procedure:
To (S)-tert-butyl 2-oxo-1-(3-(phenylethynyl)phenyl)ethylcarbamate (95 mg, 0.283 mmol) in tetrahydrofuran (5 mL) at −78° C. was added phenylmagnesium bromide (0.198 mL, 0.595 mmol) dropwise. After half of the phenylmagnesium bromide was added the stir bar stopped spinning due to a gum which formed around it. The ice bath was removed allowing the reaction to warm until the stir bar began to stir again. The addition of Grignard reagent was continued and after 1 h, a fine precipitate was evident. TLC (25% ethyl acetate/hexane; UV and phosphomolybdic acid) showed a single major spot just below starting material (Rf=0.45). After 1.5 h total, the reaction was quenched with 1N HCl (10 mL) and extracted into ethyl acetate (3×10 mL). The combined organics were washed with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo to 126 mg amber oil which was loaded with dichloromethane onto a 12 g silica gel column prepacked with 5% ethyl acetate/hexanes. Elution with 5 to 30% ethyl acetate/hexanes over 250 mL provided 62 mg tert-butyl (1S,2S)-2-hydroxy-2-phenyl-1-(3-(phenylethynyl)phenyl)ethylcarbamate as a colorless oil which was used directly in the next step.
Reaction SMILES: OC1C2C(=CC=CC=2)C(NS(C2SC=CC=2)(=O)=O)=CC=1[S:21][CH2:22][C:23]([OH:25])=[O:24].[C:26](O)(=S)C(C)O.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](/[N:42]=[C:43]2\[CH:44]=[C:45](Cl)[C:46](=[O:53])[C:47]3[C:52]\2=[CH:51][CH:50]=[CH:49][CH:48]=3)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH:42][C:43]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]([OH:53])=[C:45]([S:21][CH:22]([CH3:26])[C:23]([OH:25])=[O:24])[CH:44]=2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: CC(O)C(O)=S
Reactant: O=C(O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2ccc(Cl)cc2)c2ccccc21
Product: CC(Sc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c2ccccc2c1O)C(=O)O

Procedure:
5.2.63 2-(4-(4-chlorophenylsulfonamido)-1-hydroxynaphthalen-2-ylthio)propanoic acid (14u) was prepared according to the procedure of procedure B for 10a except using thiolactic acid and (E)-4-chloro-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)-benzenesulfonamide (12e), which afforded the title compound 41.3 mg (49%) as a white solid, m.p.: 177-179° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:36]1([CH2:43][C:44]([N:46]([CH3:48])[CH3:47])=[O:45])[CH2:42][CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:39]3[CH2:40][CH2:41][CH2:42][N:36]([CH2:43][C:44]([N:46]([CH3:48])[CH3:47])=[O:45])[CH2:37][CH2:38]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)CN1CCCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCCN(CC(=O)N(C)C)CC1
Product: Cl

Procedure:
2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-[1,4]diazepan-1-yl}-N,N-dimethyl-acetamide hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 2-[1,4]diazepan-1-yl-N,N-dimethyl-acetamide (example 20b) in an analogous manner as described in example 25. LR-MS: 678.5 [(M+H)+]